Alan Mark

Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent.

Publisher: AIP Publishing

Date: 04-01-2007

DOI: 10.1063/1.2404954

Abstract: Replica exchange methods (REMs) are increasingly used to improve s ling in molecular dynamics (MD) simulations of biomolecular systems. However, despite having been shown to be very effective on model systems, the application of REM in complex systems such as for the simulation of protein and peptide folding in explicit solvent has not been objectively tested in detail. Here we present a comparison of conventional MD and temperature replica exchange MD (T-REMD) simulations of a β-heptapeptide in explicit solvent. This system has previously been shown to undergo reversible folding on the time scales accessible to MD simulation and thus allows a direct one-to-one comparison of efficiency. The primary properties compared are the free energy of folding and the relative populations of different conformers as a function of temperature. It is found that to achieve a similar degree of precision T-REMD simulations starting from a random set of initial configurations were approximately an order of magnitude more computationally efficient than a single 800ns conventional MD simulation for this system at the lowest temperature investigated (275K). However, whereas it was found that T-REMD simulations are more than four times more efficient than multiple independent MD simulations at one temperature (300K) the actual increase in conformation s ling was only twofold. The overall gain in efficiency using REMD resulted primarily from the ordering of different conformational states over temperature, as opposed to a large increase of conformational s ling. It is also shown that in this system exchanges are accepted primarily based on (random) fluctuations within the solvent and are not strongly correlated with the instantaneous peptide conformation raising questions in regard to the efficiency of T-REMD in larger systems.

Bilayer ice and alternate liquid phases of confined water

Publisher: AIP Publishing

Date: 02-07-2003

DOI: 10.1063/1.1580101

Abstract: We report results from molecular dynamics simulations of the freezing and melting, at ambient temperature (T=300 K), of a bilayer of liquid water induced by either changing the distance between two confining parallel walls at constant lateral pressure or by lateral compression at constant plate separation. Both transitions are found to be first order. The system studied consisted of 1200 water molecules that were described by the TIP5P model. The in-plane symmetry of the oxygen atoms in the ice bilayer was found to be rhombic with a distorted in-registry arrangement. Above and below the stability region of the ice bilayer we observed two bilayer phases of liquid water that differ in the local ordering at the level of the second shell of nearest neighbors and in the density profile normal to the plane, yielding two liquid phases with different densities. These results suggest the intriguing possibility of a liquid–liquid transition of water, confined to a bilayer, at regions where the ice bilayer is unstable with respect to either of the liquid phases. In addition, we find that under the same conditions, water confined to 3–8 layers remains in the liquid phase (albeit stratification of the transverse density profile) with values of the lateral diffusion coefficient comparable to that of the bulk.

Dynamic conformations of flavin adenine dinucleotide: Simulated molecular dynamics of the flavin cofactor related to the time-resolved fluorescence characteristics

Publisher: American Chemical Society (ACS)

Date: 27-07-2002

DOI: 10.1021/JP020356S

Using Theory to Reconcile Experiment: The Structural and Thermodynamic Basis of Ligand Recognition by Phenylethanolamine N-Methyltransferase (PNMT)

Publisher: American Chemical Society (ACS)

Date: 30-03-2011

DOI: 10.1021/CT1007229

Abstract: A fundamental challenge in computational drug design is the availability of reliable and validated experimental binding and structural data against which theoretical calculations can be compared. In this work a combination of molecular dynamics (MD) simulations and free energy calculations has been used to analyze the structural and thermodynamic basis of ligand recognition by phenylethanolamine N-methyltransferase (PNMT) in an attempt to resolve uncertainties in the available binding and structural data. PNMT catalyzes the conversion of norepinephrine into epinephrine (adrenaline), and inhibitors of PNMT are of potential therapeutic importance in Alzheimer's and Parkinson's disease. Excellent agreement between the calculated and recently revised relative binding free energies to human PNMT was obtained with the average deviation between the calculated and the experimentally determined values being only 0.8 kJ/mol. In this case, the variation in the experimental data over time is much greater than the uncertainties in the theoretical estimates. The calculations have also enabled the refinement of structure-activity relationships in this system, to understand the basis of enantiomeric selectivity of substitution at position three of tetrahydroisoquinoline and to identify the role of specific structural waters. Finally, the calculations suggest that the preferred binding mode of trans-(1S,2S)-2-amino-1-tetralol is similar to that of its epimer cis-(1R,2S)-2-amino-1-tetralol and that the ligand does not adopt the novel binding mode proposed in the pdb entry 2AN5 . The work demonstrates how MD simulations and free energy calculations can be used to resolve uncertainties in experimental binding affinities, binding modes, and other aspects related to X-ray refinement and computational drug design.

Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/J.STR.2016.02.017

Probing the Pharmacological Binding Sites of P-Glycoprotein Using Umbrella Sampling Simulations

Publisher: American Chemical Society (ACS)

Date: 12-12-2019

DOI: 10.1021/ACS.JCIM.8B00624

Abstract: The human multidrug transporter P-glycoprotein (P-gp) transports over 200 chemically erse substrates, influencing their bioavailability and tissue distribution. Pharmacological studies have identified both competitive and noncompetitive P-gp substrates, but neither the precise location of the substrate binding sites, nor the basis of competitive and noncompetitive interactions has been fully characterized. Here, potential of mean force (PMF) calculations are used to identify the transport-competent minimum free energy binding locations of five compounds, Hoechst 33342, Rhodamine 123, paclitaxel, tariquidar, and verapamil to P-gp. Unrestrained molecular dynamics simulations were also performed to confirm the substrates were stable in the energy wells determined using the PMF calculations. All compounds had energy minima within the P-gp transmembrane (TM) pore. For Hoechst 33342 and Rhodamine 123, a second minimum outside the TM pore was also identified. Based on this and previous studies of nicardipine and morphine [ Subramanian et al. J. Chem. Inf. Model. 2015 , 55 , 1202 ], a general scheme that accounts for the observed noncompetitive and competitive substrate interactions with P-gp is proposed.

Molecular dynamics simulations from putative transition states of alpha-spectrin SH3 domain.

Publisher: Wiley

Date: 10-07-2007

DOI: 10.1002/PROT.21491

Abstract: A series of molecular dynamics simulations in explicit solvent were started from nine structural models of the transition state of the SH3 domain of alpha-spectrin, which were generated by Lindorff-Larsen et al. (Nat Struct Mol Biol 2004 :443-449) using molecular dynamics simulations in which experimental Phi - values were incorporated as restraints. Two of the nine models were simulated 10 times for 200 ns and the remaining models simulated two times for 200 ns. Complete folding was observed in one case, while in the other simulations partial folding or unfolding events were observed, which were characterized by a regularization of elements of secondary structure. These results are consistent with recent experimental evidence that the folding of SH3 domains involves low populated intermediate states.

Revealing the Interplay between Charge Transport, Luminescence Efficiency, and Morphology in Organic Light‐Emitting Diode Blends

Publisher: Wiley

Date: 23-12-2019

DOI: 10.1002/ADFM.201907942

Phase behavior of a phospholipid/fatty acid/water mixture studied in atomic detail.

Publisher: American Chemical Society (ACS)

Date: 19-01-2006

DOI: 10.1021/JA056619O

Abstract: Molecular dynamics simulations have been used to study the phase behavior of a dipalmitoylphosphatidylcholine (DPPC) almitic acid (PA)/water 1:2:20 mixture in atomic detail. Starting from a random solution of DPPC and PA in water, the system adopts either a gel phase at temperatures below approximately 330 K or an inverted hexagonal phase above approximately 330 K in good agreement with experiment. It has also been possible to observe the direct transformation from a gel to an inverted hexagonal phase at elevated temperature (approximately 390 K). During this transformation, a metastable fluid lamellar intermediate is observed. Interlamellar connections or stalks form spontaneously on a nanosecond time scale and subsequently elongate, leading to the formation of an inverted hexagonal phase. This work opens the possibility of studying in detail how the formation of nonlamellar phases is affected by lipid composition and (fusion) peptides and, thus, is an important step toward understanding related biological processes, such as membrane fusion.

Calcium binding to the purple membrane: A molecular dynamics study

Publisher: Wiley

Date: 14-08-2009

DOI: 10.1002/PROT.22182

Abstract: The purple membrane (PM) is a specialized membrane patch found in halophilic archaea, containing the photoreceptor bacteriorhodopsin (bR). It is long known that calcium ions bind to the PM, but their position and role remain elusive to date. Molecular dynamics simulations in conjunction with a highly detailed model of the PM have been used to investigate the stability of calcium ions placed at three proposed cation binding sites within bR, one near the Schiff base, one in the region of the proton release group, and one near Glu9. The simulations suggest that, of the sites investigated, the binding of calcium ions was most likely at the proton release group. Binding in the region of the Schiff base, while possible, was associated with significant changes in local geometry. Calcium ions placed near Glu9 in the interior of bR (simultaneously to a Ca(2+) near the Schiff base and another one near the Glu194-Glu204 site) were not stable. The results obtained are discussed in relation to recent experimental observations and theoretical considerations.

Calculation of the free energy of solvation for neutral analogs of amino acid side chains

Publisher: Wiley

Date: 20-02-2002

DOI: 10.1002/JCC.10052

Abstract: The ability of the GROMOS96 force field to reproduce partition constants between water and two less polar solvents (cyclohexane and chloroform) for analogs of 18 of the 20 naturally occurring amino acids has been investigated. The estimations of the solvation free energies in water, in cyclohexane solution, and chloroform solution are based on thermodynamic integration free energy calculations using molecular dynamics simulations. The calculations show that while the force field reproduces the experimental solvation free energies of nonpolar analogs with reasonable accuracy the solvation free energies of polar analogs in water are systematically overestimated (too positive). The dependence of the calculated free energies on the atomic partial charges was also studied.

Identification of Possible Binding Sites for Morphine and Nicardipine on the Multidrug Transporter P-Glycoprotein Using Umbrella Sampling Techniques

Publisher: American Chemical Society (ACS)

Date: 18-05-2015

DOI: 10.1021/CI5007382

Abstract: The multidrug transporter P-glycoprotein (P-gp) is central to the development of multidrug resistance in cancer. While residues essential for transport and binding have been identified, the location, composition, and specificity of potential drug binding sites are uncertain. Here molecular dynamics simulations are used to calculate the free energy profile for the binding of morphine and nicardipine to P-gp. We show that morphine and nicardipine primarily interact with key residues implicated in binding and transport from mutational studies, binding at different but overlapping sites within the transmembrane pore. Their permeation pathways were distinct but involved overlapping sets of residues. The results indicate that the binding location and permeation pathways of morphine and nicardipine are not well separated and cannot be considered as unique. This has important implications for our understanding of substrate uptake and transport by P-gp. Our results are independent of the choice of starting structure and consistent with a range of experimental studies.

Mechanism by which 2,2,2-trifluoroethanol/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study

Publisher: Proceedings of the National Academy of Sciences

Date: 26-08-2002

DOI: 10.1073/PNAS.182199699

Abstract: Molecular dynamics simulation techniques have been used to investigate the effect of 2,2,2-trifluoroethanol (TFE) as a cosolvent on the stability of three different secondary structure-forming peptides: the α-helix from Melittin, the three-stranded β-sheet peptide Betanova, and the β-hairpin 41–56 from the B1 domain of protein G. The peptides were studied in pure water and 30% (vol/vol) TFE/water mixtures at 300 K. The simulations suggest that the stabilizing effect of TFE is induced by the preferential aggregation of TFE molecules around the peptides. This coating displaces water, thereby removing alternative hydrogen-bonding partners and providing a low dielectric environment that favors the formation of intrapeptide hydrogen bonds. Because TFE interacts only weakly with nonpolar residues, hydrophobic interactions within the peptides are not disrupted. As a consequence, TFE promotes stability rather than inducing denaturation.

Definition and testing of the GROMOS force-field versions 54A7 and 54B7

Publisher: Springer Science and Business Media LLC

Date: 30-04-2011

DOI: 10.1007/S00249-011-0700-9

Abstract: New parameter sets of the GROMOS biomolecular force field, 54A7 and 54B7, are introduced. These parameter sets summarise some previously published force field modifications: The 53A6 helical propensities are corrected through new φ/ψ torsional angle terms and a modification of the N-H, C=O repulsion, a new atom type for a charged -CH(3) in the choline moiety is added, the Na(+) and Cl(-) ions are modified to reproduce the free energy of hydration, and additional improper torsional angle types for free energy calculations involving a chirality change are introduced. The new helical propensity modification is tested using the benchmark proteins hen egg-white lysozyme, fox1 RNA binding domain, chorismate mutase and the GCN4-p1 peptide. The stability of the proteins is improved in comparison with the 53A6 force field, and good agreement with a range of primary experimental data is obtained.

PyThinFilm: Automated Molecular Dynamics Simulation Protocols for the Generation of Thin Film Morphologies

Publisher: American Chemical Society (ACS)

Date: 21-12-2023

DOI: 10.1021/ACS.JCIM.2C01334

A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6

Publisher: Wiley

Date: 14-07-2004

DOI: 10.1002/JCC.20090

Abstract: Successive parameterizations of the GROMOS force field have been used successfully to simulate biomolecular systems over a long period of time. The continuing expansion of computational power with time makes it possible to compute ever more properties for an increasing variety of molecular systems with greater precision. This has led to recurrent parameterizations of the GROMOS force field all aimed at achieving better agreement with experimental data. Here we report the results of the latest, extensive reparameterization of the GROMOS force field. In contrast to the parameterization of other biomolecular force fields, this parameterization of the GROMOS force field is based primarily on reproducing the free enthalpies of hydration and apolar solvation for a range of compounds. This approach was chosen because the relative free enthalpy of solvation between polar and apolar environments is a key property in many biomolecular processes of interest, such as protein folding, biomolecular association, membrane formation, and transport over membranes. The newest parameter sets, 53A5 and 53A6, were optimized by first fitting to reproduce the thermodynamic properties of pure liquids of a range of small polar molecules and the solvation free enthalpies of amino acid analogs in cyclohexane (53A5). The partial charges were then adjusted to reproduce the hydration free enthalpies in water (53A6). Both parameter sets are fully documented, and the differences between these and previous parameter sets are discussed.

Understanding the accumulation of P-glycoprotein substrates within cells: The effect of cholesterol on membrane partitioning

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/J.BBAMEM.2015.12.025

Abstract: The apparent activity of the multidrug transporter P-glycoprotein (P-gp) is enhanced by the presence of cholesterol. Whether this is due to the direct effect of cholesterol on the activity of P-gp, its effect on the local concentration of substrate in the membrane, or its effect on the rate of entry of the drug into the cell, is unknown. In this study, molecular dynamics simulation techniques coupled with potential of mean force calculations have been used to investigate the role of cholesterol in the movement of four P-gp substrates across a POPC bilayer in the presence or absence of 10% cholesterol. The simulations suggest that the presence of cholesterol lowers the free energy associated with entering the middle of the bilayer in a substrate-specific manner. These findings suggest that P-gp substrates may preferentially accumulate in cholesterol-rich regions of the membrane, which may explain its enhanced transport activity.

Ion transport across transmembrane pores.

Publisher: Elsevier BV

Date: 06-2007

DOI: 10.1529/BIOPHYSJ.106.101295

Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for Its Inhibition of Human Voltage-gated Sodium Channel Na(V)1.7

Publisher: Elsevier BV

Date: 08-2016

DOI: 10.1074/JBC.M116.729095

Testing and validation of the Automated Topology Builder (ATB) version 2.0: prediction of hydration free enthalpies

Publisher: Springer Science and Business Media LLC

Date: 30-01-2014

DOI: 10.1007/S10822-014-9713-7

Abstract: To test and validate the Automated force field Topology Builder and Repository (ATB compbio.biosci.uq.edu.au/atb/ ) the hydration free enthalpies for a set of 214 drug-like molecules, including 47 molecules that form part of the SAMPL4 challenge have been estimated using thermodynamic integration and compared to experiment. The calculations were performed using a fully automated protocol that incorporated a dynamic analysis of the convergence and integration error in the selection of intermediate points. The system has been designed and implemented such that hydration free enthalpies can be obtained without manual intervention following the submission of a molecule to the ATB. The overall average unsigned error (AUE) using ATB 2.0 topologies for the complete set of 214 molecules was 6.7 kJ/mol and for molecules within the SAMPL4 7.5 kJ/mol. The root mean square error (RMSE) was 9.5 and 10.0 kJ/mol respectively. However, for molecules containing functional groups that form part of the main GROMOS force field the AUE was 3.4 kJ/mol and the RMSE was 4.0 kJ/mol. This suggests it will be possible to further refine the parameters provided by the ATB based on hydration free enthalpies.

Application of mean field boundary potentials in simulations of lipid vesicles

Publisher: American Chemical Society (ACS)

Date: 30-05-2008

DOI: 10.1021/JP0758519

Abstract: A method is presented to enhance the efficiency of simulations of lipid vesicles. The method increases computational speed by eliminating water molecules that either surround the vesicle or reside in the interior of the vesicle, without altering the properties of the water at the membrane interface. Specifically, mean field force approximation (MFFA) boundary potentials are used to replace both the internal and external excess bulk solvent. In addition to reducing the cost of simulating preformed vesicles, the molding effect of the boundary potentials also enhances the formation and equilibration of vesicles from random solutions of lipid in water. Vesicles with diameters in the range from 20 to 60 nm were obtained on a nanosecond time scale, without any noticeable effect of the boundary potentials on their structure.

Effect of Surface Roughness on Light-Absorber Orientation in an Organic Photovoltaic Film

Publisher: American Chemical Society (ACS)

Date: 10-07-2019

DOI: 10.1021/ACS.CHEMMATER.9B01337

On the Validation of Molecular Dynamics Simulations of Saturated and cis-Monounsaturated Phosphatidylcholine Lipid Bilayers: A Comparison with Experiment

Publisher: American Chemical Society (ACS)

Date: 23-11-2010

DOI: 10.1021/CT900487A

Abstract: Molecular dynamics simulations of fully hydrated pure bilayers of four widely studied phospholipids, 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC) using a recent revision of the GROMOS96 force field are reported. It is shown that the force field reproduces the structure and the hydration of bilayers formed by each of the four lipids with high accuracy. Specifically, the solvation and the orientation of the dipole of the phosphocholine headgroup and of the ester carbonyls show that the structure of the primary hydration shell in the simulations closely matches experimental findings. This work highlights the need to reproduce a broad range of properties beyond the area per lipid, which is poorly defined experimentally, and to consider the effect of system size and s ling times well beyond those commonly used.

A new cytokine receptor activation paradigm: Activation of JAK2 by the growth hormone receptor

Publisher: Elsevier BV

Date: 11-2014

DOI: 10.1016/J.CYTO.2014.07.227

The conformation of the extracellular binding domain of Death Receptor 5 in the presence and absence of the activating ligand TRAIL: A molecular dynamics study

Publisher: Wiley

Date: 08-2008

DOI: 10.1002/PROT.21541

Abstract: The Death Receptor 5 (DR5), a member of tumor necrosis factor receptor (TNFR) superfamily of receptors, triggers apoptosis (programmed cell death) when stimulated by its tridentate ligand TRAIL. Until recently it was generally assumed that the activation of DR5 resulted from the recruitment of three independent receptor units, leading to the trimerization of intracellular domains. However, there is mounting evidence to suggest that, in the absence of ligand, such cytokine receptors primarily reside as preformed complexes. In this work, molecular dynamics simulations of the TRAIL-DR5 complex, the unbound receptor trimer and in idual receptor monomers are compared to gain insight in the mechanism of activation. The results suggest that, in the absence of TRAIL, DR5 has a strong propensity to self-associate and that this is primarily mediated through interactions of the membrane proximal domains. The association of the free receptors leads to a loss of the threefold symmetry found within the receptor-ligand complex. The simulations suggest that the primary role of TRAIL is to induce threefold-symmetry within the DR5 complex and to constrain the receptor to a specific conformation. The implications of this in terms of the mechanism by which the receptor switches from an inactive to an active state are discussed.

CONVERGENCE PROPERTIES OF FREE-ENERGY CALCULATIONS - ALPHA-CYCLODEXTRIN COMPLEXES AS A CASE-STUDY

Publisher: American Chemical Society (ACS)

Date: 07-1994

DOI: 10.1021/JA00093A032

Elucidating the Spatial Arrangement of Emitter Molecules in Organic Light‐Emitting Diode Films

Publisher: Wiley

Date: 07-02-2017

DOI: 10.1002/ANGE.201610727

Response of microbial membranes to butanol: Interdigitation: vs. Disorder

Publisher: Royal Society of Chemistry (RSC)

Date: 2019

DOI: 10.1039/C9CP01469A

Abstract: Elucidating butanol interactions with lipid bilayers will inform membrane engineering approaches for improving butanol tolerance in industrial fermentations.

Relative stability of protein structures determined by X-ray crystallography or NMR spectroscopy: A molecular dynamics simulation study

Publisher: Wiley

Date: 05-08-2003

DOI: 10.1002/PROT.10496

Abstract: The relative stability of protein structures determined by either X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy has been investigated by using molecular dynamics simulation techniques. Published structures of 34 proteins containing between 50 and 100 residues have been evaluated. The proteins selected represent a mixture of secondary structure types including all alpha, all beta, and alpha/beta. The proteins selected do not contain cysteine-cysteine bridges. In addition, any crystallographic waters, metal ions, cofactors, or bound ligands were removed before the systems were simulated. The stability of the structures was evaluated by simulating, under identical conditions, each of the proteins for at least 5 ns in explicit solvent. It is found that not only do NMR-derived structures have, on average, higher internal strain than structures determined by X-ray crystallography but that a significant proportion of the structures are unstable and rapidly erge in simulations.

Photoactivation of the photoactive yellow protein: Why photon absorption triggers a trans-to-cis lsomerization of the chromophore in the protein

Publisher: American Chemical Society (ACS)

Date: 11-03-2004

DOI: 10.1021/JA039557F

Abstract: Atomistic QM/MM simulations have been carried out on the complete photocycle of Photoactive Yellow Protein, a bacterial photoreceptor, in which blue light triggers isomerization of a covalently bound chromophore. The "chemical role" of the protein cavity in the control of the photoisomerization step has been elucidated. Isomerization is facilitated due to preferential electrostatic stabilization of the chromophore's excited state by the guanidium group of Arg52, located just above the negatively charged chromophore ring. In vacuo isomerization does not occur. Isomerization of the double bond is enhanced relative to isomerization of a single bond due to the steric interactions between the phenyl ring of the chromophore and the side chains of Arg52 and Phe62. In the isomerized configuration (ground-state cis), a proton transfer from Glu46 to the chromophore is far more probable than in the initial configuration (ground-state trans). It is this proton transfer that initiates the conformational changes within the protein, which are believed to lead to signaling.

Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors

Publisher: AIP Publishing

Date: 11-07-2011

DOI: 10.1063/1.3604534

Abstract: The relative binding free energy between two ligands to a specific protein can be obtained using various computational methods. The more accurate and also computationally more demanding techniques are the so-called free energy methods which use conformational s ling from molecular dynamics or Monte Carlo simulations to generate thermodynamic averages. Two such widely applied methods are the thermodynamic integration (TI) and the recently introduced enveloping distribution s ling (EDS) methods. In both cases relative binding free energies are obtained through the alchemical perturbations of one ligand into another in water and inside the binding pocket of the protein. TI requires many separate simulations and the specification of a pathway along which the system is perturbed from one ligand to another. Using the EDS approach, only a single automatically derived reference state enveloping both end states needs to be s led. In addition, the choice of an optimal pathway in TI calculations is not trivial and a poor choice may lead to poor convergence along the pathway. Given this, EDS is expected to be a valuable and computationally efficient alternative to TI. In this study, the performances of these two methods are compared using the binding of ten tetrahydroisoquinoline derivatives to phenylethanolamine N-transferase as an ex le. The ligands involve a erse set of functional groups leading to a wide range of free energy differences. In addition, two different schemes to determine automatically the EDS reference state parameters and two different topology approaches are compared.

The revised Penrose-Hameroff orchestrated objective-reduction proposal for human consciousness is not scientifically justified Comment on Consciousness in the universe: A review of the 'Orch OR' theory by Hameroff and Penrose

Publisher: Elsevier BV

Date: 03-2014

DOI: 10.1016/J.PLREV.2013.11.003

Signal transduction in the photoactive yellow protein. I. Photon absorption and the isomerization of the chromophore

Publisher: Wiley

Date: 29-05-2002

DOI: 10.1002/PROT.10136

Abstract: Molecular dynamics simulation techniques together with time-dependent density functional theory calculations have been used to investigate the effect of photon absorption by a 4-hydroxy-cinnamic acid chromophore on the structural properties of the photoactive yellow protein (PYP) from Ectothiorodospira halophila. The calculations suggest that the protein not only modifies the absorption spectrum of the chromophore but also regulates the subsequent isomerization of the chromophore by stabilizing the isomerization transition state. Although signaling from PYP is thought to involve partial unfolding of the protein, the mechanical effects accompanying isomerization do not appear to directly destabilize the protein.

Mechanism of activation of protein kinase JAK2 by the growth hormone receptor

Publisher: American Association for the Advancement of Science (AAAS)

Date: 16-05-2014

DOI: 10.1126/SCIENCE.1249783

Abstract: Signaling from JAK (Janus kinase) protein kinases to STAT (signal transducers and activators of transcription) transcription factors is key to many aspects of biology and medicine, yet the mechanism by which cytokine receptors initiate signaling is enigmatic. We present a complete mechanistic model for activation of receptor-bound JAK2, based on an archetypal cytokine receptor, the growth hormone receptor. For this, we used fluorescence resonance energy transfer to monitor positioning of the JAK2 binding motif in the receptor dimer, substitution of the receptor extracellular domains with Jun zippers to control the position of its transmembrane (TM) helices, atomistic modeling of TM helix movements, and docking of the crystal structures of the JAK2 kinase and its inhibitory pseudokinase domain with an opposing kinase-pseudokinase domain pair. Activation of the receptor dimer induced a separation of its JAK2 binding motifs, driven by a ligand-induced transition from a parallel TM helix pair to a left-handed crossover arrangement. This separation leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation. This model may well generalize to other class I cytokine receptors.

Folding study of an Aib-rich peptide in DMSO by molecular dynamics simulations

Publisher: Wiley

Date: 02-2001

DOI: 10.1034/J.1399-3011.2001.00793.X

Abstract: To evaluate the ability of molecular dynamics (MD) simulations using atomic force-fields to correctly predict stable folded conformations of a peptide in solution, we show results from MD simulations of the reversible folding of an octapeptide rich in alpha-aminoisobutyric acid (2-amino-2-methyl-propanoic acid, Aib) solvated in di-methyl-sulfoxide (DMSO). This solvent generally prevents the formation of secondary structure, whereas Aib-rich peptides show a high propensity to form secondary structural elements, in particular 3(10)- and alpha-helical structures. Aib is, moreover, achiral, so that Aib-rich peptides can form left- or right-handed helices depending on the overall composition of the peptide, the temperature, and the solvation conditions. This makes the system an interesting case to study the ensembles of peptide conformations as a function of temperature by MD simulation. Simulations involving the folding and unfolding of the peptide were performed starting from two initial structures, a right-handed alpha-helical structure and an extended structure, at three temperatures, 298 K, 340 K, and 380 K, and the results are compared with experimental nuclear magnetic resonance (NMR) data measured at 298 K and 340 K. The simulations generally reproduce the available experimental nuclear Overhauser effect (NOE) data, even when a wide range of conformations is s led at each temperature. The importance of adequate statistical s ling in order to reliably interpret the experimental data is discussed.

An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0

Publisher: American Chemical Society (ACS)

Date: 15-11-2011

DOI: 10.1021/CT200196M

Abstract: The Automated force field Topology Builder (ATB, compbio.biosci.uq.edu.au/atb ) is a Web-accessible server that can provide topologies and parameters for a wide range of molecules appropriate for use in molecular simulations, computational drug design, and X-ray refinement. The ATB has three primary functions: (1) to act as a repository for molecules that have been parametrized as part of the GROMOS family of force fields, (2) to act as a repository for pre-equilibrated systems for use as starting configurations in molecular dynamics simulations (solvent mixtures, lipid systems pre-equilibrated to adopt a specific phase, etc.), and (3) to generate force field descriptions of novel molecules compatible with the GROMOS family of force fields in a variety of formats (GROMOS, GROMACS, and CNS). Force field descriptions of novel molecules are derived using a multistep process in which results from quantum mechanical (QM) calculations are combined with a knowledge-based approach to ensure compatibility (as far as possible) with a specific parameter set of the GROMOS force field. The ATB has several unique features: (1) It requires that the user stipulate the protonation and tautomeric states of the molecule. (2) The symmetry of the molecule is analyzed to ensure that equivalent atoms are assigned identical parameters. (3) Charge groups are assigned automatically. (4) Where the assignment of a given parameter is ambiguous, a range of possible alternatives is provided. The ATB also provides several validation tools to assist the user to assess the degree to which the topology generated may be appropriate for a given task. In addition to detailing the steps involved in generating a force field topology compatible with a specific GROMOS parameter set (GROMOS 53A6), the challenges involved in the automatic generation of force field parameters for atomic simulations in general are discussed.

Effect of High Pressure on Fully Hydrated DPPC and POPC Bilayers

Publisher: American Chemical Society (ACS)

Date: 31-12-2011

DOI: 10.1021/JP110002Q

Abstract: Enhanced hydrostatic pressure can induce phase transitions in hydrated lipid bilayers especially those composed of saturated phospholipids. In this work, the phase behavior of fully hydrated DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and POPC (2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine) bilayers as a function of pressure up to 3000 atm has been examined in atomic detail on time scales of up to 1.0 μs, using the molecular dynamics simulation technique. DPPC bilayers formed a rippled gel-like phase comprising a minor disordered fluid-like region and a major ordered gel-like region at 1000 atm, a partially interdigitated gel-like phase at 2000 atm, and a gel-like phase with most of the lipid acyl chains tilted with respect to the plane of the bilayer at 3000 atm. POPC bilayers formed a rippled gel-like phase at 1800, 2400, and 3000 atm. The phase behavior observed for both DPPC and POPC bilayers is in agreement with experiment. The simulations provide insight into the structural changes of DPPC and POPC bilayers as a function of pressure and demonstrate the ability to model biologically relevant lipid systems under high hydrostatic pressure.

COMPUTER-SIMULATION OF PROTEIN MOTION

Publisher: Elsevier BV

Date: 09-1995

DOI: 10.1016/0010-4655(95)00055-K

Electrofreezing of confined water

Publisher: AIP Publishing

Date: 30-03-2004

DOI: 10.1063/1.1687315

Abstract: We report results from molecular dynamics simulations of the freezing transition of TIP5P water molecules confined between two parallel plates under the influence of a homogeneous external electric field, with magnitude of 5 V/nm, along the lateral direction. For water confined to a thickness of a trilayer we find two different phases of ice at a temperature of T=280 K. The transformation between the two, proton-ordered, ice phases is found to be a strong first-order transition. The low-density ice phase is built from hexagonal rings parallel to the confining walls and corresponds to the structure of cubic ice. The high-density ice phase has an in-plane rhombic symmetry of the oxygen atoms and larger distortion of hydrogen bond angles. The short-range order of the two ice phases is the same as the local structure of the two bilayer phases of liquid water found recently in the absence of an electric field [J. Chem. Phys. 119, 1694 (2003)]. These high- and low-density phases of water differ in local ordering at the level of the second shell of nearest neighbors. The results reported in this paper, show a close similarity between the local structure of the liquid phase and the short-range order of the corresponding solid phase. This similarity might be enhanced in water due to the deep attractive well characterizing hydrogen bond interactions. We also investigate the low-density ice phase confined to a thickness of 4, 5, and 8 molecular layers under the influence of an electric field at T=300 K. In general, we find that the degree of ordering decreases as the distance between the two confining walls increases.

Membrane-binding properties of gating modifier and pore-blocking toxins: Membrane interaction is not a prerequisite for modification of channel gating

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/J.BBAMEM.2016.02.002

Abstract: Many venom peptides are potent and selective inhibitors of voltage-gated ion channels, including channels that are validated therapeutic targets for treatment of a wide range of human diseases. However, the development of novel venom-peptide-based therapeutics requires an understanding of their mechanism of action. In the case of voltage-gated ion channels, venom peptides act either as pore blockers that bind to the extracellular side of the channel pore or gating modifiers that bind to one or more of the membrane-embedded voltage sensor domains. In the case of gating modifiers, it has been debated whether the peptide must partition into the membrane to reach its binding site. In this study, we used surface plasmon resonance, fluorescence spectroscopy and molecular dynamics to directly compare the lipid-binding properties of two gating modifiers (μ-TRTX-Hd1a and ProTx-I) and two pore blockers (ShK and KIIIA). Only ProTx-I was found to bind to model membranes. Our results provide further evidence that the ability to insert into the lipid bilayer is not a requirement to be a gating modifier. In addition, we characterised the surface of ProTx-I that mediates its interaction with neutral and anionic phospholipid membranes and show that it preferentially interacts with anionic lipids.

Simulation studies of pore and domain formation in a phospholipid monolayer

Publisher: AIP Publishing

Date: 17-12-2005

DOI: 10.1063/1.1825992

Abstract: Despite extensive study the phase behavior of phospholipid monolayers at an air–water interface is still not fully understood. In particular recent vibrational sum-frequency generation (VSFG) spectra of DPPC monolayers as a function of area density show a sharp transition in the order of the lipid chains at 1.10 nm2/molecule. This is in a region where the lateral pressure as a function of area is effectively constant. We have investigated the nature of this transition by studying the phase behavior of DPPC monolayers as a function of area density using molecular-dynamics simulations. The changes in order within the monolayer as a function of area density correlate well with the experimental signal. At 0.58 nm2/molecule we observe the onset of lateral separation of highly ordered and disordered lipids, indicating the coexistence of a gel-like liquid condensed and a fluidlike liquid expanded phase. At 0.97 nm2/molecule the monolayer ruptures, marking the onset of the liquid–gas (G) coexistence region. This is much earlier than suggested by fluorescence microscopy results and implies that at the point of rupture, the initial pores have an equilibrium size smaller than ∼500 nm in diameter. The rupture of the monolayer leads to a sharp increase in the overall lipid order that explains the sharp transition observed in the VSFG measurements. VSFG measurements thus may represent a sensitive means to determine the onset of the liquid–gas (G) coexistence region for such systems.

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a.

Publisher: American Chemical Society (ACS)

Date: 24-12-2015

DOI: 10.1021/ACS.JCIM.5B00529

Abstract: Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptide-channel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental information with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing ion channel (ASIC) 1a as a case study, we have examined the effect of different combinations of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-channel interactions. For this, we have analyzed over 200,000 water-refined docked structures obtained with various amounts and types of restraints of the peptide-channel complex predicted using the docking program HADDOCK. We found that increasing the number of restraints or even the use of pairwise interaction data resulted in only a modest improvement in the likelihood of finding a structure within a given accuracy. This suggests that shape complementarity and the force field make a large contribution to the accuracy of the predicted structure. The results also showed that there are large variations in the accuracy of the predicted structure depending on the precise combination of residues used as restraints. Finally, we reflect on the limitations of relying on geometric criteria such as root-mean square deviations to assess the accuracy of docking procedures. We propose that in addition to currently used measures, the likelihood of finding a structure within a given level of accuracy should be also used to evaluate docking methods.

Turning the growth hormone receptor on: Evidence that hormone binding induces subunit rotation

Publisher: Wiley

Date: 19-11-2010

DOI: 10.1002/PROT.22636

Abstract: Atomistic molecular dynamics simulations have been used to investigate the conformational changes associated with the binding of human growth hormone (hGH) to the extracellular domains (ECD) of the human growth hormone receptor (hGHR), thereby shedding light on the mechanism of activation. It is shown that the removal of hGH from the hormone-bound receptor complex results in a counter-clockwise rotation of the twosubunits relative to each other by 30 degrees -64 degrees (average 45 degrees +/- 14 degrees), in close agreement in terms of both the magnitude and direction of the rotation with that proposed based on mutagenesis experiments. In addition to providing evidence to support a rotational activation mechanism, the simulations have enabled the nature of the interaction interfaces in both the cytokine-bound and unliganded hGHR states to be analyzed in detail.

Evolution and Morphology of Thin Films Formed by Solvent Evaporation: An Organic Semiconductor Case Study

Publisher: American Chemical Society (ACS)

Date: 26-08-2020

DOI: 10.1021/ACSAMI.0C08454

Simulation of pore formation in lipid bilayers by mechanical stress and electric fields

Publisher: American Chemical Society (ACS)

Date: 05-2003

DOI: 10.1021/JA029504I

Abstract: We describe computer simulations of pore formation and membrane rupture of phospholipid bilayers under mechanical and electrical stress. On the nanosecond simulation time scale, pores are induced by a lateral pressure exceeding -200 bar or by an applied electric field of 0.5 V/nm.

Toroidal pores formed by antimicrobial peptides show significant disorder

Publisher: Elsevier BV

Date: 10-2008

DOI: 10.1016/J.BBAMEM.2008.06.007

Abstract: A large variety of antimicrobial peptides have been shown to act, at least in vitro, by poration of the lipid membrane. The nanometre size of these pores, however, complicates their structural characterization by experimental techniques. Here we use molecular dynamics simulations, to study the interaction of a specific class of antimicrobial peptides, melittin, with a dipalmitoylphosphatidylcholine bilayer in atomic detail. We show that transmembrane pores spontaneously form above a critical peptide to lipid ratio. The lipid molecules bend inwards to form a toroidally shaped pore but with only one or two peptides lining the pore. This is in strong contrast to the traditional models of toroidal pores in which the peptides are assumed to adopt a transmembrane orientation. We find that peptide aggregation, either prior or after binding to the membrane surface, is a prerequisite to pore formation. The presence of a stable helical secondary structure of the peptide, however is not. Furthermore, results obtained with modified peptides point to the importance of electrostatic interactions in the poration process. Removing the charges of the basic amino-acid residues of melittin prevents pore formation. It was also found that in the absence of counter ions pores not only form more rapidly but lead to membrane rupture. The rupture process occurs via a novel recursive poration pathway, which we coin the Droste mechanism.

Missing Fragments: Detecting Cooperative Binding in Fragment-Based Drug Design

Publisher: American Chemical Society (ACS)

Date: 16-02-2012

DOI: 10.1021/ML300015U

The Effect of Environment on the Recognition and Binding of Vancomycin to Native and Resistant Forms of Lipid II

Publisher: Elsevier BV

Date: 12-2011

DOI: 10.1016/J.BPJ.2011.10.047

Refining homology models by combining replica-exchange molecular dynamics and statistical potentials

Publisher: Wiley

Date: 12-03-2008

DOI: 10.1002/PROT.22005

Bestimmung von Strukturinformation aus experimentellen Messdaten für Biomoleküle

Publisher: Wiley

Date: 08-11-2016

DOI: 10.1002/ANGE.201601828

Antimicrobial peptides in action

Publisher: American Chemical Society (ACS)

Date: 25-08-2006

DOI: 10.1021/JA062927Q

Abstract: Molecular dynamics simulations of the magainin MG-H2 peptide interacting with a model phospholipid membrane have been used to investigate the mechanism by which antimicrobial peptides act. Multiple copies of the peptide were randomly placed in solution close to the membrane. The peptide readily bound to the membrane, and above a certain concentration, the peptide was observed to cooperatively induce the formation of a nanometer-sized, toroidally shaped pore in the bilayer. In sharp contrast with the commonly accepted model of a toroidal pore, only one peptide was typically found near the center of the pore. The remaining peptides lay close to the edge of the pore, maintaining a predominantly parallel orientation with respect to the membrane.

Probing the free energy landscape of the FBP28WW domain using multiple techniques.

Publisher: Wiley

Date: 22-10-2009

DOI: 10.1002/JCC.21128

Abstract: The free-energy landscape of a small protein, the FBP 28 WW domain, has been explored using molecular dynamics (MD) simulations with alternative descriptions of the molecule. The molecular models used range from coarse-grained to all-atom with either an implicit or explicit treatment of the solvent. S ling of conformation space was performed using both conventional and temperature-replica exchange MD simulations. Experimental chemical shifts and NOEs were used to validate the simulations, and experimental phi values both for validation and as restraints. This combination of different approaches has provided insight into the free energy landscape and barriers encountered by the protein during folding and enabled the characterization of native, denatured and transition states which are compatible with the available experimental data. All the molecular models used stabilize well defined native and denatured basins however, the degree of agreement with the available experimental data varies. While the most detailed, explicit solvent model predicts the data reasonably accurately, it does not fold despite a simulation time 10 times that of the experimental folding time. The less detailed models performed poorly relative to the explicit solvent model: an implicit solvent model stabilizes a ground state which differs from the experimental native state, and a structure-based model underestimates the size of the barrier between the two states. The use of experimental phi values both as restraints, and to extract structures from unfolding simulations, result in conformations which, although not necessarily true transition states, appear to share the geometrical characteristics of transition state structures. In addition to characterizing the native, transition and denatured states of this particular system in this work, the advantages and limitations of using varying levels of representation are discussed.

FLUCTUATION AND CROSS-CORRELATION ANALYSIS OF PROTEIN MOTIONS OBSERVED IN NANOSECOND MOLECULAR-DYNAMICS SIMULATIONS

Publisher: Elsevier BV

Date: 09-1995

DOI: 10.1006/JMBI.1995.0514

Abstract: Nanosecond molecular dynamics simulations of bovine pancreatic trypsin inhibitor and lysozyme in water are analyzed in terms of backbone atomic positional fluctuations and dynamical cross-correlations. It is found that although the molecular systems are stable, B-factors calculated over a time period as long as 500 ps are not representative for the motions within the proteins. This is especially true for the most mobile residues. On a nanosecond time-scale, the B-factors calculated from the simulations of the proteins in solution are considerably larger than those obtained by structure refinement of the proteins in crystals, based on X-ray data. The time evolution of the atomic fluctuations shows that for large portions of the proteins under study, atomic positional fluctuations are not yet converged after a nanosecond. Cross-correlations do not converge faster than the fluctuations themselves. Most display very erratic behavior if the s ling covers less than about 200 ps. It is also shown that inclusion of mobile atoms into the procedure used to remove rigid-body motion from the simulation can lead to spurious correlations between the motions of the atoms at the surface of the protein.

The future of advertising campaigns: The role of AI-generated images in advertising creative

Publisher: Intellect

Date: 08-2023

DOI: 10.1386/JPM_00003_1

Abstract: Computational creativity is a growing component of new artificial intelligence (AI) technologies that allow a machine to render creative constructs such as music, text and images. A rapidly growing area of computational creativity is AI text-to-image engines capable of producing realistic imagery that can now meet the standard of human quality outputs. DALL-E 2, built by OpenAI, is a leader in the field and offers commercial access to AI-produced images. To understand the impact of engines such as DALL-E 2 on advertising agencies and their creative workflows, we conducted a series of focus groups with Aotearoa, New Zealand-based advertising agencies exploring creative practitioners’ considerations on the capability of the DALL-E 2 text-to-image technology. An existing Volkswagen advertising c aign called ‘Small but Ferocious’ that used ‘blended’ animals as a visual metaphor for their economical yet powerful ‘TSI’ engines was expanded in a ‘faux’ continuation of the c aign. Four new images produced by DALL-E 2 were presented to creatives attending the focus groups. Participants were then asked about these new creative-AI assets concerning image quality, creative production and collaborative models. A thematic analysis of the comments from the focus groups was conducted and elicited three themes: aesthetics, creative practice and human vs. machine . Participants’ responses revealed that they were both excited and concerned about DALL-E 2’s capability in image production, its effect on creative workflows and the role of the human vs. machine in generating creative outputs. The result was a clear sense of inevitability for how creative roles will change as computational creativity systems, such as DALL-E 2, advance and are adopted into agency workflows.

GROMOS Force Field

Publisher: Wiley

Date: 25-09-2002

DOI: 10.1002/0470845015.CGA011

Effect of Methyl-Branched Fatty Acids on the Structure of Lipid Bilayers

Publisher: American Chemical Society (ACS)

Date: 19-11-2014

DOI: 10.1021/JP503910R

Abstract: Methyl-branched fatty acids are widespread in prokaryotic membranes. Although anteiso and iso branching (that is on the antepenultimate and penultimate carbons) and the presence of multiple methyl branches in the phytanoyl chain are known to modify the thermotropic behavior and enhance the fluidity of lipid bilayers, little is known about the effect of methyl branching on the structure of lipid bilayers. In this study, molecular dynamics simulations are used to examine systematically the impact of one or more methyl branches at different positions along the sn-1 palmitoyl chain on the structural properties of a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayer. It is found that methyl branching reduces lipid condensation, decreases the bilayer thickness, and lowers chain ordering. Branching also results in the formation of kinks at the branching point, thereby enhancing the fluidity of lipid bilayers. Furthermore, this effect varies in a methyl-position-dependent fashion. In the case of polymethylated chains, the simulations suggest that if the gap between the methyl groups is sufficient (two or three carbons), the effects of the methyl branches are additive and equivalent to the combined effect of the corresponding monomethyl-branched lipids.

Predicting the Prevalence of Alternative Warfarin Tautomers in Solution

Publisher: American Chemical Society (ACS)

Date: 12-07-2018

DOI: 10.1021/ACS.JCTC.8B00453

Abstract: Warfarin, a widely used oral anticoagulant, is prescribed as a racemic mixture. Each enantiomer of neutral Warfarin can exist in 20 possible tautomeric states leading to complex pharmacokinetics and uncertainty as to the relevant species under different conditions. Here, the ability of alternative computational approaches to predict the preferred tautomeric form(s) of neutral Warfarin in different solvents is examined. It is shown that varying the method used to estimate the heat of formation in vacuum (direct or via homodesmic reactions), whether entropic corrections were included, and the method used to estimate the free enthalpy of solvation (i.e., PCM, COSMO, or SMD implicit models or explicit solvent) lead to large differences in the predicted rank and relative populations of the tautomers. In this case, only a combination of the enthalpy of formation using homodesmic reactions and explicit solvent to estimate the free enthalpy of solvation yielded results compatible with the available experimental data. The work also suggests that a small but significant subset of the possible Warfarin tautomers are likely to be physiologically relevant.

Some Like It Hot: The Effect of Sterols and Hopanoids on Lipid Ordering at High Temperature

Publisher: American Chemical Society (ACS)

Date: 03-11-2014

DOI: 10.1021/JZ5020778

Abstract: Sterols and hopanoids have been suggested to reinforce membranes and protect against unfavorable environmental conditions. In particular, hopanoids are found in high concentrations in membranes of thermotolerant and thermophilic bacteria. However, the mechanism whereby sterols and hopanoids stabilize membranes at elevated temperatures is poorly understood. Here, the effect of temperature on the ordering of lipids in bilayers containing cholesterol or the hopanoids bacteriohopanetetrol and diplopterol was explored using molecular dynamics simulations. It is shown that cholesterol induces a high level of ordering over a wide range of temperatures. Bacteriohopanetetrol promotes order within the lipid tails but enhances fluid-like properties of the head groups at high temperatures. In contrast, diplopterol partitions in the midplane of the bilayer. This suggests that in idual hopanoids fulfill distinct functions in membranes, with the ordering properties of bacteriohopanetetrol being particularly well suited to maintain the integrity of membranes at temperatures preferred by thermotolerant and thermophilic bacteria.

CONFORMATIONAL FLEXIBILITY OF AQUEOUS MONOMERIC AND DIMERIC INSULIN - A MOLECULAR-DYNAMICS STUDY

Publisher: American Chemical Society (ACS)

Date: 11-1991

DOI: 10.1021/BI00109A009

Abstract: A series of molecular dynamics simulations have been used to investigate the nature of monomeric and dimeric insulin in aqueous solution. It is shown that in the absence of crystal contacts both monomeric and dimeric insulin have a high degree of intrinsic flexibility. Neither of the two monomer conformations of 2Zn crystalline insulin appears to be favored in solution nor is the asymmetry of the crystal dimer reduced in the absence of crystal contacts. A shift is observed in the relative positions of molecules 1 and 2 in the dimer compared with that found in the crystal, which may have consequences for the prediction of the effects of mutants in the monomer-monomer interface designed to alter the self-association properties of insulin.

Does Tautomerization of FapyG Influence Its Mutagenicity?

Publisher: Wiley

Date: 14-05-2014

DOI: 10.1002/CPHC.201400045

Abstract: Oxidative degradation of guanine to 2,6-diamino-4-oxo-5-formamidopyrimidine (FapyG) is believed to be mutagenic. It has been proposed recently that the enol tautomer of FapyG is mainly responsible for this effect leading to a guanine-to-thymine mutation (T. H. Gehrke, U. Lischke, K. L. Gasteiger, S. Schneider, S. Arnold, H. C. Muller, D. S. Stephenson, H. Zipse, T. Carell, Nat. Chem. Biol.- 2013, 9, 455-461). Here, density functional methods suggest that the enol tautomer of FapyG might not be responsible for the proposed guanine-to-thymine mutation. Instead, it might result in a guanine-to-adenine mutation.

Refinement of homology-based protein structures by molecular dynamics simulation techniques

Publisher: Wiley

Date: 2004

DOI: 10.1110/PS.03381404

Abstract: The use of classical molecular dynamics simulations, performed in explicit water, for the refinement of structural models of proteins generated ab initio or based on homology has been investigated. The study involved a test set of 15 proteins that were previously used by Baker and coworkers to assess the efficiency of the ROSETTA method for ab initio protein structure prediction. For each protein, four models generated using the ROSETTA procedure were simulated for periods of between 5 and 400 nsec in explicit solvent, under identical conditions. In addition, the experimentally determined structure and the experimentally derived structure in which the side chains of all residues had been deleted and then regenerated using the WHATIF program were simulated and used as controls. A significant improvement in the deviation of the model structures from the experimentally determined structures was observed in several cases. In addition, it was found that in certain cases in which the experimental structure deviated rapidly from the initial structure in the simulations, indicating internal strain, the structures were more stable after regenerating the side-chain positions. Overall, the results indicate that molecular dynamics simulations on a tens to hundreds of nanoseconds time scale are useful for the refinement of homology or ab initio models of small to medium-size proteins.

Activating the Prolactin Receptor: Effect of the Ligand on the Conformation of the Extracellular Domain

Publisher: American Chemical Society (ACS)

Date: 03-09-2010

DOI: 10.1021/CT1003934

Abstract: The prolactin receptor resides on the surface of the cell as a preformed dimer. This suggests that cell signaling is triggered by conformational changes within the extracellular domain of the receptors. Here, by using atomistic molecular dynamics simulations, we show that the removal of the ligand placental lactogen from the dimeric form of the prolactin receptor results in a relative reorientation of the two extracellular domains by 20-30°, which corresponds to a clockwise rotation of the domains with respect to each other. Such a mechanism of activation for the prolactin receptor is similar to that proposed previously in the case of the growth hormone receptor. In addition to the effect of the removal of the ligand, the mechanical coupling between the extracellular and transmembrane domains within a model membrane was also examined.

The CC domain structure from the wheat stem rust resistance protein Sr33 challenges paradigms for dimerization in plant NLR proteins

Publisher: Proceedings of the National Academy of Sciences

Date: 17-10-2016

DOI: 10.1073/PNAS.1609922113

Abstract: Plants and animals use intracellular immunity receptors, known as nucleotide-binding oligomerization domain-like receptors (NLRs), to defend themselves against invading microbes. In this study, we report the solution structure of the N-terminal coiled-coil (CC) domain from the wheat stem rust resistance protein Sr33. Remarkably, this structure differs substantially from the published crystal structure of the equivalent region from the orthologous barley powdery mildew resistance protein MLA10. Using a structural, biophysical, and functional approach, we compare the Sr33 CC domain with other structurally defined NLR CC domains. Collectively, this work redefines our current understanding of the structure and function of plant NLR CC domains, which has significant implications for future studies into this important class of defense receptors.

Deriving Structural Information from Experimentally Measured Data on Biomolecules.

Publisher: Wiley

Date: 08-11-2016

DOI: 10.1002/ANIE.201601828

Abstract: During the past half century, the number and accuracy of experimental techniques that can deliver values of observables for biomolecular systems have been steadily increasing. The conversion of a measured value Q

INTERACTION OF ANALOGS OF NICOTINAMIDE ADENINE-DINUCLEOTIDE PHOSPHATE WITH DIHYDROFOLATE-REDUCTASE FROM ESCHERICHIA-COLI

Publisher: American Chemical Society (ACS)

Date: 11-09-1984

DOI: 10.1021/BI00314A014

Mimicking the action of GroEL in molecular dynamics simulations: Application to the refinement of protein structures

Publisher: Wiley

Date: 03-2006

DOI: 10.1110/PS.051721006

Activation of the Epidermal Growth Factor Receptor: A Series of Twists and Turns

Publisher: American Chemical Society (ACS)

Date: 17-04-2014

DOI: 10.1021/BI401632Z

Abstract: The cell surface epidermal growth factor receptor (EGFR) plays a critical role in cell development and oncogenesis. The binding of growth factors to the EGFR results in a mechanical signal being transmitted through the plasma membrane. In this study, atomistic molecular dynamics simulations have been used to investigate the conformational changes associated with the binding of the epidermal growth factor (EGF) and transforming growth factor α (TGFα) to the EGFR. In the simulations, the removal of the EGF and TGFα from the extracellular domain of the EGFR homodimer led to a relative rotation of the protomers of 16-35° about the dimerization axis. The three N-terminal domains that make up the extracellular region of the receptor undergo essentially rigid-body motion. The dimerization interface itself was found to be largely unaffected by the removal of the ligand. In most simulations, the rotation within the dimer was associated with an opening of the cytokine-binding sites. On the basis of these simulations, a simple mechanical model that explains the coupling between the binding of ligand and the motions in the extracellular domains is proposed.

The Molecular Origin of Anisotropic Emission in an Organic Light-Emitting Diode

Publisher: American Chemical Society (ACS)

Date: 18-09-2017

DOI: 10.1021/ACS.NANOLETT.7B03528

Abstract: Atomistic nonequilibrium molecular dynamics simulations have been used to model the induction of molecular orientation anisotropy within the emission layer of an organic light-emitting diode (OLED) formed by vapor deposition. Two emitter species were compared: racemic fac-tris(2-phenylpyridine)iridium(III) (Ir(ppy)

On the characterization of host-guest complexes: surface tension, calorimetry, and molecular dynamics of cyclodextrins with a non-ionic surfactant.

Publisher: American Chemical Society (ACS)

Date: 12-04-2007

DOI: 10.1021/JP0688815

Abstract: Three host-guest systems have been characterized using surface tension (sigma), calorimetry, and molecular dynamics simulations (MD). The hosts were three native cyclodextrins (CD) and the guest the non-ionic carbohydrate surfactant octyl-beta-d-glucopyranoside. It is shown that, for any host-guest system, a rough screening of the most probable complex stoichiometries can be obtained in a model free form, using only calorimetric data. The sigma data were analyzed using a model that includes a newly proposed adsorption isotherm. The equilibrium constants for several stoichiometries were simultaneously obtained through fitting the sigma data. For alpha- and beta-CD, the predominant species is 1:1 and to a lesser extent 2:1, disregarding the existence of the 1:2. For gamma-CD, the 1:2 species dominates, the other two being also present. In an attempt to confirm these results, 10 ns MD simulations for each CD were performed using seven different starting conformations. The MD stable conformations agree with the results found from the experimental data. In one case, the spontaneous dissociation-formation of a complex was observed. Analysis of the trajectories indicates that hydrophobic interactions are primarily responsible for the formation and stability of the inclusion complexes. For the 2:1 species, intermolecular H-bonds between CD molecules result in a tight packed structure where their original truncated cone shape is lost in favor of a cylindrical geometry. Together, the results clearly demonstrate that the often used assumption of considering only a 1:1 species is inappropriate.

CALCULATION OF RELATIVE FREE-ENERGY VIA INDIRECT PATHWAYS

Publisher: AIP Publishing

Date: 03-1991

DOI: 10.1063/1.459753

Abstract: A general method is presented to reduce the simulation time required to compute the relative free energy between two states X and Y of a molecular system by computer simulation. Although the free energy difference ΔAx→y is, in principle, independent of the pathway chosen to change X into Y, in practice its choice strongly affects the accuracy of the obtained ΔA value. The optimum path is the one for which the relaxation time of the system τsystem attains a minimum, allowing the system to remain as close as possible near equilibrium during a simulation. Downscaling the relevant parts of the potential energy function before the change from X to Y is made, and upscaling afterwards is a rather general way to shorten τsystem and thus save computing time. For a model system of butane like molecules the proposed procedure is more than 1 order of magnitude more efficient than the conventional technique of direct interconversion from state X to state Y.

Calculation of the redox potential of the protein azurin and some mutants

Publisher: Wiley

Date: 06-04-2005

DOI: 10.1002/CBIC.200400244

Abstract: Azurin from Pseudomonas aeruginosa is a small 128-residue, copper-containing protein. Its redox potential can be modified by mutating the protein. Free-energy calculations based on classical molecular-dynamics simulations of the protein and from mutants in aqueous solution at different pH values were used to compute relative redox potentials. The precision of the free-energy calculations with the lambda coupling-parameter approach is evaluated as function of the number and sequence of lambda values, the s ling time and initial conditions. It is found that the precision is critically dependent on the relaxation of hydrogen-bonding networks when changing the atomic-charge distribution due to a change of redox state or pH value. The errors in the free energies range from 1 to 10 k(B)T, depending on the type of process. Only qualitative estimates of the change in redox potential by protein mutation can be obtained.

Unraveling exciton processes in Ir(ppy)3:CBP OLED films upon photoexcitation

Publisher: AIP Publishing

Date: 22-04-2021

DOI: 10.1063/5.0044177

Abstract: Emissive layers in phosphorescent organic light-emitting diodes commonly make use of guest–host blends such as Ir(ppy)3:CBP to achieve high external quantum efficiencies. However, while the Ir(ppy)3:CBP blend has been studied experimentally, crucial questions remain regarding how exciton diffusion is dependent on the distribution of the guest in the host, which can currently only be addressed at the atomic level via computational modeling. In this work, kinetic Monte Carlo simulations are utilized to gain insight into exciton diffusion in Ir(ppy)3:CBP blend films. The effects of both guest concentration and exciton density on various system properties are analyzed, including the probability of singlet excitons being converted to triplets, and the probability of those triplets decaying radiatively. Significantly, these simulations suggest that triplet diffusion occurs almost exclusively via guest–guest Dexter transfer and that concentration quenching of triplets induced by guest–guest intermolecular dipole-dipole interactions has a negligible effect at high exciton densities due to the prevalence of triplet–triplet annihilation. Furthermore, results for vacuum deposited morphologies derived from molecular dynamics simulations are compared to the results obtained using a simple cubic lattice approximation with randomly distributed guest molecules. We show that while differences in host-based processes such as singlet diffusion are observed, overall, the results on the fate of the excitons are in good agreement for the two morphology types, particularly for guest-based processes at low guest concentrations where guest clustering is limited.

Real Cost of Speed: The Effect of a Time-Saving Multiple-Time-Stepping Algorithm on the Accuracy of Molecular Dynamics Simulations

Publisher: American Chemical Society (ACS)

Date: 26-05-2017

DOI: 10.1021/ACS.JCTC.7B00178

Abstract: To enhance efficiency in molecular dynamics simulations, forces that vary slowly are often evaluated less often than those that vary rapidly. We show that the multiple-time-step algorithm implemented in recent versions of GROMACS results in significant differences in the collective properties of a system under conditions where the system was previously stable. The implications of changing the simulation algorithm without assessment of potential artifacts on the parametrization and transferability of effective force fields are discussed.

CONSTRUCTION AND MOLECULAR-DYNAMICS SIMULATION OF CALMODULIN IN THE EXTENDED AND IN A BENT CONFORMATION

Publisher: Wiley

Date: 03-1992

DOI: 10.1111/J.1432-1033.1992.TB16714.X

Abstract: Analysis of sequence similarity and comparison of the three-dimensional (3D) structures of troponin C and calmodulin have revealed a sequence in the central helix of calmodulin with a high probability for bending. The three amino acids known to form a bend in the N-terminal portion of troponin C are also found in the central helix of calmodulin. The modelling of a bent calmodulin structure, using the dihedral angles of the three residues in the bend of troponin C as a 3D template, results in a conformation of calmodulin where the N- and C-terminal domains are able to form contacts. Dynamics simulations starting from the X-ray structure of calmodulin and from the modelled bent calmodulin were carried out to compare flexibility and correlated movements of Ca2+ in the binding loops. Both conformations of calmodulin remained stable during the period of simulation. In the simulation of calmodulin in the extended form, the motions of the Ca2+ atoms in the two domains (Ca2+1 and Ca2+2 in one domain, and Ca2+3 and Ca2+4 in the other) are correlated. In the simulation of the bent form, an additional correlation between the Ca atoms in the two different domains is observed. The results are compatible with the occurrence of a bent conformation of calmodulin in the presence of targets, and with increased Ca2+ affinity and cooperativity of the Ca(2+)-binding loops in the calmodulin-peptide complexes.

Molecular view of hexagonal phase formation in phospholipid membranes

Publisher: Elsevier BV

Date: 12-2004

DOI: 10.1529/BIOPHYSJ.104.048710

THE SELF-ASSOCIATION OF ZINC-FREE BOVINE INSULIN - A SINGLE MODEL BASED ON INTERACTIONS IN THE CRYSTAL THAT DESCRIBES THE ASSOCIATION PATTERN IN SOLUTION AT PH 2, 7 AND 10

Publisher: Elsevier BV

Date: 08-1987

DOI: 10.1016/0301-4622(87)80051-0

Abstract: Sedimentation equilibrium studies are used to establish that a new pattern for the self-association of zinc-free insulin in solution is applicable over a wide range of conditions of pH, ionic strength and temperature. In this pattern, which is based on information from the existing literature on the X-ray crystal structure of insulin, the insulin monomer is viewed as having two distinct faces both capable of self-interaction. Sedimentation equilibrium experiments were analysed using expressions formulated for this association pattern that describe the dependence of weight average molecular weight and monomer concentration on total protein concentration. It has thereby been possible to obtain values for the two association constants which govern the system for each set of conditions studied, due allowance having been made for composition dependent non-ideality effects. Furthermore, by relating the pH, temperature and ionic strength dependence of the association constants with properties of various amino acid residues on the surface of the insulin monomer, it has also been possible to assign tentatively each constant to a particular reaction domain.

Determining the Structure of Interfacial Peptide Films: Comparing Neutron Reflectometry and Molecular Dynamics Simulations

Publisher: American Chemical Society (ACS)

Date: 14-08-2014

DOI: 10.1021/LA501715H

Abstract: The peptides AM1 and Lac21E self-organize into switchable films at an air-water interface. In an earlier study, it was proposed that both AM1 and Lac21E formed monolayers of α-helical peptides based on consistency with neutron reflectivity data. In this article, molecular dynamics simulations of assemblies of helical and nonhelical AM1 and Lac21E at an air-water interface suggest some tendency for the peptides to spontaneously adopt an α-helical conformation. However, irrespective of the structure of the peptides, the simulations reproduced not only the structural properties of the films (thickness and distribution of the hydrophobic and hydrophilic amino acids) but also the experimental neutron reflectivity measurements at different contrast variations. This suggests that neutron reflectometry alone cannot be used to determine the structure of the peptides in this case. However, together with molecular dynamics simulations, it is possible to obtain a detailed understanding of peptide films at an atomic level.

The mechanism of vesicle fusion as revealed by molecular dynamics simulations

Publisher: American Chemical Society (ACS)

Date: 15-08-2003

DOI: 10.1021/JA036138+

Abstract: We describe molecular dynamics simulations elucidating the molecular details of the process of fusion for small lipid vesicles. The simulations are based on a coarse grained (CG) lipid model that accurately represents the lamellar state of a variety of phospholipids and enables us to observe intermediate stages during fusion at near atomic detail. Simulations were conducted on a variety of systems containing common phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysoPC, and mixtures of the above. The fusion intermediates found are in general agreement with the stalk-pore mechanism. Transient pores sometimes form adjacent to the stalk, however, resulting in the mixing of lipids from the outer and inner monolayers. The speed of stalk formation and the opening of the fusion pore can be modulated by altering the lipid composition in qualitative agreement with experimental observations.

Mimicking the action of folding chaperones in molecular dynamics simulations: Application to the refinement of homology-based protein structures

Publisher: Wiley

Date: 04-2004

DOI: 10.1110/PS.03449904

Electrophoretic mobility does not always reflect the charge on an oil droplet.

Publisher: Elsevier BV

Date: 02-2007

DOI: 10.1016/J.JCIS.2007.10.035

Abstract: Electrophoresis is widely used to determine the electrostatic potential of colloidal particles. Oil droplets in pure water show negative or positive electrophoretic mobilities depending on the pH. This is commonly attributed to the adsorption of hydroxyl or hydronium ions, resulting in a negative or positive surface charge, respectively. This explanation, however, is not in agreement with the difference in isoelectric point and point of zero charge observed in experiment. Here we present molecular dynamics simulations of oil droplets in water in the presence of an external electric field but in the absence of any ions. The simulations reproduce the negative sign and the order of magnitude of the oil droplet mobilities at the point of zero charge in experiment. The electrostatic potential in the oil with respect to the water phase, induced by anisotropic dipole orientation in the interface, is positive. Our results suggest that electrophoretic mobility does not always reflect the net charge or electrostatic potential of a suspended liquid droplet and, thus, the interpretation of electrophoresis in terms of purely continuum effects may need to be reevaluated.

The Characterization of Modified Starch Branching Enzymes: Toward the Control of Starch Chain-Length Distributions

Publisher: Public Library of Science (PLoS)

Date: 13-04-2015

DOI: 10.1371/JOURNAL.PONE.0125507

The binary mixing behavior of phospholipids in a bilayer: A molecular dynamics study

Publisher: American Chemical Society (ACS)

Date: 22-01-2004

DOI: 10.1021/JP0366926

Stability of SIV gp32 fusion-peptide single-layer protofibrils as monitored by molecular-dynamics simulations

Publisher: Wiley

Date: 03-01-2005

DOI: 10.1002/ANIE.200461935

Alternative Mechanisms for the Interaction of the Cell-Penetrating Peptides Penetratin and the TAT Peptide with Lipid Bilayers

Publisher: Elsevier BV

Date: 07-2009

DOI: 10.1016/J.BPJ.2009.03.059

Developments in Glycopeptide Antibiotics

Publisher: American Chemical Society (ACS)

Date: 24-01-2018

DOI: 10.1021/ACSINFECDIS.7B00258

Engineering Transferable Atomic Force Fields: Empirical Optimization of Hydrocarbon Lennard–Jones Interactions by Direct Mapping of Parameter Space

Publisher: American Chemical Society (ACS)

Date: 22-06-2023

DOI: 10.1021/ACS.JCTC.3C00427

The role of histidine residues in low-pH-mediated viral membrane fusion

Publisher: Elsevier BV

Date: 10-2006

DOI: 10.1016/J.STR.2006.07.011

Abstract: A central event in the invasion of a host cell by an enveloped virus is the fusion of viral and cell membranes. For many viruses, membrane fusion is driven by specific viral surface proteins that undergo large-scale conformational rearrangements, triggered by exposure to low pH in the endosome upon internalization. Here, we present evidence suggesting that in both class I (helical hairpin proteins) and class II (beta-structure-rich proteins) pH-dependent fusion proteins the protonation of specific histidine residues triggers fusion via an analogous molecular mechanism. These histidines are located in the vicinity of positively charged residues in the prefusion conformation, and they subsequently form salt bridges with negatively charged residues in the postfusion conformation. The molecular surfaces involved in the corresponding structural rearrangements leading to fusion are highly conserved and thus might provide a suitable common target for the design of antivirals, which could be active against a erse range of pathogenic viruses.

Factors That Affect the Degree of Twist in beta-Sheet Structures: A Molecular Dynamics Simulation Study of a Cross-beta Filament of the GNNQQNY Peptide

Publisher: American Chemical Society (ACS)

Date: 20-01-2009

DOI: 10.1021/JP8078259

Abstract: By exploiting the recent availability of the crystal structure of a cross-beta filament of the GNNQQNY peptide fragment of the yeast prion protein Sup35, possible factors affecting the twisting of beta-sheets structures have been analyzed. The advantage of this system is that it is composed entirely of beta-sheet and thus free of potential ambiguities present in systems studied previously. In the crystal the cross-beta filament consists of antiparallel beta-sheets formed by parallel and in register peptides lying perpendicular to the long axis of the filament. The results of a series of molecular dynamics simulations performed under different conditions indicate that in the absence of crystal packing interactions there is no free energy barrier against twisting for the cross-beta filament found planar in the crystal. More specifically, we find that there is only a small change in enthalpy (<3 kJ mol(-1) per residue) for twists in the range 0-12 degrees with the planar form (in the crystal environment) being enthalpically stabilized. In contrast, entropic contributions, in particular those associated with an increase in backbone dynamics upon twisting, stabilize the twisted form. The degree of twist was found to vary depending on the environmental conditions as the result from an apparent subtle interplay of multiple small contributions. These observations are consistent with the different degrees of twist observed in beta-sheets both in native protein structures and amyloid fibrils.

Morphology of a Bulk Heterojunction Photovoltaic Cell with Low Donor Concentration

Publisher: American Chemical Society (ACS)

Date: 28-08-2018

DOI: 10.1021/ACSAMI.8B10321

Abstract: Atomistic nonequilibrium molecular dynamics simulations have been used to model the morphology of small-molecule bulk heterojunction films formed by vapor deposition as used in organic photovoltaics. Films comprising C

Automated partial atomic charge assignment for drug-like molecules: A fast knapsack approach

Publisher: Springer Science and Business Media LLC

Date: 05-02-2019

DOI: 10.1186/S13015-019-0138-7

Simulation of gel phase formation and melting in lipid bilayers using a coarse grained model

Publisher: Elsevier BV

Date: 06-2005

DOI: 10.1016/J.CHEMPHYSLIP.2005.03.001

Abstract: The transformation between a gel and a fluid phase in dipalmitoyl-phosphatidylcholine (DPPC) bilayers has been simulated using a coarse grained (CG) model by cooling bilayer patches composed of up to 8000 lipids. The critical step in the transformation process is the nucleation of a gel cluster consisting of 20-80 lipids, spanning both monolayers. After the formation of the critical cluster, a fast growth regime is entered. Growth slows when multiple gel domains start interacting, forming a percolating network. Long-lived fluid domains remain trapped and can be metastable on a microsecond time scale. From the temperature dependence of the rate of cluster growth, the line tension of the fluid-gel interface was estimated to be 3+/-2 pN. The reverse process is observed when heating the gel phase. No evidence is found for a hexatic phase as an intermediate stage of melting. The hysteresis observed in the freezing and melting transformation is found to depend both on the system size and on the time scale of the simulation. Extrapolating to macroscopic length and time scales, the transition temperature for heating and cooling converges to 295+/-5 K, in semi-quantitative agreement with the experimental value for DPPC (315 K). The phase transformation is associated with a drop in lateral mobility of the lipids by two orders of magnitude, and an increase in the rotational correlation time of the same order of magnitude. The lipid headgroups, however, remain fluid. These observations are in agreement with experimental findings, and show that the nature of the ordered phase obtained with the CG model is indeed a gel rather than a crystalline phase. Simulations performed at different levels of hydration furthermore show that the gel phase is stabilized at low hydration. A simulation of a small DPPC vesicle reveals that curvature has the opposite effect.

The relative effect of sterols and hopanoids on lipid bilayers: when comparable is not identical.

Publisher: American Chemical Society (ACS)

Date: 03-12-2013

DOI: 10.1021/JP409748D

Abstract: Sterols are the hallmarks of eukaryotic membranes where they are often found in specialized functional microdomains of the plasma membrane called lipid rafts. Despite some notable exceptions, prokaryotes lack sterols. However, growing evidence has suggested the existence of raft-like domains in the plasma membrane of bacteria. A structurally related family of triterpenoids found in some bacteria called hopanoids has long been assumed to be bacterial surrogates for sterols in membranes. Although the effect of sterols, in particular cholesterol, on lipid bilayers has been extensively characterized through experimental and simulation studies, those of hopanoids have hardly been investigated. In this study, molecular dynamics simulations are used to examine the effect of two hopanoids, diploptene (hop-22(29)-ene) and bacteriohopanetetrol ((32R,33S,34S)-bacteriohopane-32,33,34,35-tetrol), on a model bilayer. The results are compared with those obtained for cholesterol and a pure phosphatidylcholine bilayer. It is shown that diploptene and bacteriohopanetetrol behave very differently under the conditions simulated. Whereas bacteriohopanetetrol adopted a cholesterol-like upright orientation in the bilayer, diploptene partitioned between the two leaflets inside the bilayer. Analysis of various structural properties (area per lipid, electron density profile, tilt angle of the lipids, and conformation and order parameters of the phosphatidylcholine tails) in bacteriohopanetetrol- and cholesterol-containing bilayers indicates that the condensing and ordering effect of bacteriohopanetetrol is weaker than that of cholesterol. The simulations suggest that the chemical ersity of hopanoids may lead to a broader range of functional roles in bacterial membranes than sterols in eukaryotic membranes.

THE SELF-ASSOCIATION OF ZINC-FREE BOVINE INSULIN - 4 MODEL PATTERNS AND THEIR SIGNIFICANCE

Publisher: Walter de Gruyter GmbH

Date: 1990

DOI: 10.1515/BCHM3.1990.371.2.1165

Abstract: Data fitting procedures both with and without correction for non-ideality are applied to experimentally measured concentration distributions of zinc-free insulin obtained over a wide range of experimental conditions (pH 2, 7, and 10, ionic strengths 0.05 and 0.1, t = 25 degrees C and 37 degrees C) using four different model self-association patterns based on known physico-chemical properties of insulin in solution and patterns already in the literature. It is shown that three of these must be considered satisfactory descriptions of the insulin system of equilibria in aqueous solution as judged by critical curve-fitting criteria. The significant differences, as well as common features of these are assessed by comparing the distribution of monomeric and polymeric forms at three insulin concentrations of practical utility, "serum", "pharmacological", and "physicochemical". The value of analysing protein self-association with the aid of explicit equations formulated for a specific model, even when it cannot be demonstrated to be unique, is discussed with particular reference to osmotic pressure measurements made by others on insulins modified by recombinant DNA techniques aimed at making them essentially monomeric.

Molecular simulation as an aid to experimentalists

Publisher: Elsevier BV

Date: 04-2008

DOI: 10.1016/J.SBI.2007.12.007

Abstract: Computer-based molecular simulation techniques are increasingly used to interpret experimental data on biomolecular systems at an atomic level. Direct comparison between experiment and simulation is, however, seldom straightforward. The available experimental data are limited in scope and generally correspond to averages over both time and space. A critical analysis of the various factors that may influence the apparent degree of agreement between the results of simulations and experimentally measured quantities is presented and illustrated using ex les from recent literature.

Histidine protonation and the activation of viral fusion proteins

Publisher: Portland Press Ltd.

Date: 22-01-2008

DOI: 10.1042/BST0360043

Abstract: Many viral fusion proteins only become activated under mildly acidic condition (pH 4.5–6.5) close to the pKa of histidine side-chain protonation. Analysis of the sequences and structures of influenza HA (haemagglutinin) and flaviviral envelope glycoproteins has led to the identification of a number of histidine residues that are not only fully conserved themselves but have local environments that are also highly conserved [K mann, Mueller, Mark, Young and Kobe (2006) Structure 14, 1481–1487]. Here, we summarize studies aimed at determining the role, if any, that protonation of these potential switch histidine residues plays in the low-pH-dependent conformational changes associated with fusion activation of a flaviviral envelope protein. Specifically, we report on MD (Molecular Dynamics) simulations of the DEN2 (dengue virus type 2) envelope protein ectodomain sE (soluble E) performed under varied pH conditions designed to test the histidine switch hypothesis of K mann et al. (2006).

The reliability of molecular dynamics simulations of the multidrug transporter P-glycoprotein in a membrane environment

Publisher: Public Library of Science (PLoS)

Date: 25-01-2018

DOI: 10.1371/JOURNAL.PONE.0191882

Molecular structure of the lecithin ripple phase

Publisher: Proceedings of the National Academy of Sciences

Date: 04-04-2005

DOI: 10.1073/PNAS.0408249102

Abstract: Molecular dynamics simulations of lecithin lipid bilayers in water as they are cooled from the liquid crystalline phase show the spontaneous formation of rippled bilayers. The ripple consists of two domains of different length and orientation, connected by a kink. The organization of the lipids in one domain of the ripple is found to be that of a splayed gel in the other domain the lipids are gel-like and fully interdigitated. In the concave part of the kink region between the domains the lipids are disordered. The results are consistent with the experimental information available and provide an atomic-level model that may be tested by further experiments.

Does isoprene protect plant membranes from thermal shock? A molecular dynamics study

Publisher: Elsevier BV

Date: 02-2007

DOI: 10.1016/J.BBAMEM.2006.09.023

Abstract: The question of why plants release isoprene when heat stressed has been continuously debated for more than half a century. In this work we use molecular dynamics simulation techniques to directly investigate the interaction between isoprene and a model phospholipid membrane in atomic detail. It is found that isoprene partitions preferentially in the center of the membrane and in a dose dependent manner enhances the order within the membrane without significantly changing the dynamical properties of the system. At a concentration of 20 mol% isoprene (16 isoprene molecules per 64 lipid molecules) the effect of the addition of isoprene on the membrane order is equivalent to a reduction in temperature of 10 K, rising to a reduction of 30 K at 43 mol% isoprene. The significance of the work is that it provides for the first time direct evidence that isoprene stabilizes lipid membranes and reduces the likelihood of a phospholipid membrane undergoing a heat induced phase transition. Furthermore it provides a clear mechanistic picture as to why plants specifically utilize isoprene for this purpose.

Molecular Dynamics Unlocks Atomic Level Self-Assembly of the Exopolysaccharide Matrix of Water-Treatment Granular Biofilms

Publisher: American Chemical Society (ACS)

Date: 22-05-2012

DOI: 10.1021/BM3005808

Abstract: Biofilm formation, in which bacteria are embedded within an extracellular matrix, is the default form of microbial life in most natural and engineered habitats. In this work, atomistic molecular dynamics simulations were employed to examine the self-assembly of the polysaccharide Granulan to provide insight into the molecular interactions that lead to biofilm formation. Granulan is a major gel forming matrix component of granular microbial biofilms found in used-water treatment systems. Molecular dynamics simulations showed that Granulan forms an antiparallel double helix stabilized by complementary hydrogen bonds between the β-glucosamine of one strand and the N-acetyl-β-galactosamine-2-acetoamido-2-deoxy-α-galactopyranuronic pair of the other in both the presence and absence of Ca(2+). It is shown that Ca(2+) binds primarily to the carboxyl group of the terminal hexuronic acid of the sugar branch and that interactions between branches mediated by Ca(2+) suggest a possible mechanism for strengthening gels by facilitating interhelical bridging.

The Effect of Environment on the Structure of a Membrane Protein: P-Glycoprotein under Physiological Conditions

Publisher: American Chemical Society (ACS)

Date: 11-06-2012

DOI: 10.1021/CT300254Y

Abstract: The stability of the crystal structure of the multidrug transporter P-glycoprotein proposed by Aller et al. (PDBid 3G5U ) has been examined under different environmental conditions using molecular dynamics. We show that in the presence of the detergent cholate, the structure of P-glycoprotein solved at pH 7.5 is stable. However, when incorporated into a cholesterol-enriched POPC membrane in the presence of 150 mM NaCl, the structure rapidly deforms. Only when the simulation conditions closely matched the experimental conditions under which P-glycoprotein is transport active was a stable conformation obtained. Specifically, the presence of Mg(2+), which bound to distinct sites in the nucleotide binding domains (NBDs), and the double protonation of the catalytic histidines (His583 and His1228) and His149 were required. While the structure obtained in a membrane environment under these conditions is very similar to the crystal structure of Aller et al., there are several key differences. The NBDs are in direct contact, reminiscent of the open state of MalK. The angle between the transmembrane domains is also increased, resulting in an outward motion of the intracellular loops. Notably, the structures obtained from the simulations provide a better match to a range of experimental cross-linking data than does the original 3G5U-a crystal structure. This work highlights the effect small changes in environmental conditions can have of the conformation of a membrane protein and the importance of representing the experimental conditions appropriately in modeling studies.

How sensitive are nanosecond molecular dynamics simulations of proteins to changes in the force field?

Publisher: American Chemical Society (ACS)

Date: 05-2007

DOI: 10.1021/JP068580V

Abstract: The sensitivity of molecular dynamics simulations to variations in the force field has been examined in relation to a set of 36 structures corresponding to 31 proteins simulated by using different versions of the GROMOS force field. The three parameter sets used (43a1, 53a5, and 53a6) differ significantly in regard to the nonbonded parameters for polar functional groups and their ability to reproduce the correct solvation and partitioning behavior of small molecular analogues of the amino acid side chains. Despite the differences in the force field parameters no major differences could be detected in a wide range of structural properties such as the root-mean-square deviation from the experimental structure, radii of gyration, solvent accessible surface, secondary structure, or hydrogen bond propensities on a 5 to 10 ns time scale. The small differences that were observed correlated primarily with the presence of charged residues as opposed to residues that differed most between the parameter sets. The work highlights the variation that can be observed in nanosecond simulations of protein systems and implications of this for force field validation, as well as for the analysis of protein simulations in general.

Do All X-ray Structures of Protein-Ligand Complexes Represent Functional States? EPOR, a Case Study

Publisher: Elsevier BV

Date: 02-2017

DOI: 10.1016/J.BPJ.2016.12.042

PREDICTION OF THE ACTIVITY AND STABILITY EFFECTS OF SITE-DIRECTED MUTAGENESIS ON A PROTEIN CORE

Publisher: Elsevier BV

Date: 09-1992

DOI: 10.1016/0022-2836(92)90895-Q

Abstract: When theoretical methods are used to predict the properties of a given system, such as the effects of the substitution of a specific amino acid on the activity or stability of a protein as a whole, the accuracy of the prediction is directly dependent on the validity of the underlying model. A common error, however, is to attempt to improve a basically crude model by performing one aspect of the calculation in a rigorous manner. The accuracy of the model as a whole will remain limited by the crudest approximation or weakest assumption. To demonstrate the principle that nothing can be gained by performing extensive calculations using a basically crude underlying model we compare the predictive power of three models in relation to activity and stability data for 78 triple-site sequence variants of the lambda-repressor protein. This system has recently been analysed in terms of a conceptionally simple, but computationally elaborate model for the prediction of the energy of a protein in which amino acid residues in the core of the protein have been mutated. We show that comparable, if not better agreement with the experimental data can be reached using either of two much simpler models, based on straightforward structural considerations, which do not require elaborate calculations on a computer.

Enumerating common molecular substructures

Publisher: PeerJ

Date: 13-09-2017

DOI: 10.7287/PEERJ.PREPRINTS.3250V1

Abstract: Finding and enumerating common molecular substructures is an important task in cheminformatics, where small molecules are often modeled as molecular graphs. We introduce the problem of enumerating all maximal k-common molecular fragments of a pair of molecular graphs. A k-common fragment is a common connected induced subgraph that consists of a common core and a common k-neighborhood. It is thus a generalization of the NP-hard task to enumerate all maximal common connected induced subgraphs (MCCIS) of two graphs, which corresponds to the k = 0 case. We extend the MCCIS enumeration algorithm by Ina Koch and apply algorithm engineering techniques to solve practical instances fast for the general k 0 case, which is relevant, for ex le, for automatically generating force field topologies for molecular dynamics (MD) simulations. We find that our methods achieve good performance on a real-world benchmark of all-against-all comparisons of 255 molecules. Our software is available under the LGPL open source license at nitram/mogli .

Comparative study of generalized Born models: Protein dynamics

Publisher: Proceedings of the National Academy of Sciences

Date: 06-04-2005

DOI: 10.1073/PNAS.0408857102

Abstract: In this work, we compare the results of molecular dynamics simulations involving the application of three generalized Born (GB) models to 10 different proteins. The three GB models, the Still, HCT, and modified analytical generalized Born models, were implemented in the computationally efficient gromacs package. The performance of each model was assessed from the backbone rms deviation from the native structure, the number of native hydrogen bonds retained in the simulation, and the experimental and calculated radius of gyration. Analysis of variance (ANOVA) was used to analyze the results of the simulations. The rms deviation measure was found to be unable to distinguish the quality of the results obtained with the three different GB models, whereas the number of native hydrogen bonds and radius of gyration yielded a statistically meaningful discrimination among models. Our results suggest that, of the three, modified analytical generalized Born yields the best agreement between calculated and experimentally derived structures. More generally, our study highlights the need both to evaluate the effects of different variables on the results of simulations and to verify that the results of molecular dynamics simulations are statistically meaningful.

Validation of Molecular Simulation: An Overview of Issues

Publisher: Wiley

Date: 27-12-2018

DOI: 10.1002/ANIE.201702945

Abstract: Computer simulation of molecular systems enables structure-energy-function relationships of molecular processes to be described at the sub-atomic, atomic, supra-atomic, or supra-molecular level. To interpret results of such simulations appropriately, the quality of the calculated properties must be evaluated. This depends on the way the simulations are performed and on the way they are validated by comparison to values Q

Understanding binding affinity: A combined isothermal titration calorimetry/molecular dynamics study of the binding of a series of hydrophobically modified benzamidinium chloride inhibitors to trypsin

Publisher: American Chemical Society (ACS)

Date: 09-08-2003

DOI: 10.1021/JA034676G

Abstract: The binding of a series of p-alkylbenzamidinium chloride inhibitors to the serine proteinase trypsin over a range of temperatures has been studied using isothermal titration (micro)calorimetry and molecular dynamics simulation techniques. The inhibitors have small structural variations at the para position of the benzamidinium ion. They show small differences in relative binding affinity but large compensating differences in enthalpy and entropy. Binding affinity decreases with increased branching at the first carbon but increases with increasing the length of a linear alkyl substituent, suggesting that steric hindrance and hydrophobic interactions play dominant roles in binding. Structural analysis showed that the backbone of the enzyme was unaffected by the change of the para substituent. In addition, binding does not correlate strongly with octanol/water partition data. To further characterize this system, the change in the heat capacity on binding, the change in solvent-accessible surface area on binding, the effect of inhibitor binding on the hydration of the active site, the pK(a) of His57, and interactions within the catalytic triad have been investigated. Although the changes in inhibitor structure are small, it is demonstrated that simple concepts such as steric hindrance, hydrophobicity, and buried surface area are insufficient to explain the binding data. Other factors, such as access to the binding site and the cost of dehydration of the active site, are of equal or greater importance.

Understanding the Effect of pH on the Solubility and Aggregation Extent of Humic Acid in Solution by Combining Simulation and the Experiment

Publisher: American Chemical Society (ACS)

Date: 04-01-2022

DOI: 10.1021/ACS.EST.1C05938

Abstract: Molecular dynamics (MD) simulations were performed to investigate the dynamics of humic acid (HA) in an aqueous solution and the influence of pH, temperature, and HA concentration. The HA model employed in MD simulations was chosen and validated using experimental chemical composition data and Fourier transform infrared (FTIR) spectra. The simulations showed that the HA molecule has a strong propensity to adopt a compact conformation in water independent of pH, while the aggregation of HA was found to be pH-dependent. At high pH, the ionized HAs assembled into a thread-like structure, maximizing contact with water. At low pH, the neutral HAs formed a droplet-like aggregate, minimizing contact with the solvent. The simulation results are consistent with experimental data from dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM) imaging. This work provides new insight into the folding and aggregation of HA as a function of pH and a molecular-level understanding of the relationship between the acidity and the structure, solubility, and aggregation of HA, with direct implications for HA-based remediation strategies of contaminated sites.

Vancomycin: ligand recognition, dimerization and super-complex formation

Publisher: Wiley

Date: 11-02-2013

DOI: 10.1111/FEBS.12121

Abstract: The antibiotic vancomycin targets lipid II, blocking cell wall synthesis in Gram-positive bacteria. Despite extensive study, questions remain regarding how it recognizes its primary ligand and what is the most biologically relevant form of vancomycin. In this study, molecular dynamics simulation techniques have been used to examine the process of ligand binding and dimerization of vancomycin. Starting from one or more vancomycin monomers in solution, together with different peptide ligands derived from lipid II, the simulations predict the structures of the ligated monomeric and dimeric complexes to within 0.1 nm rmsd of the structures determined experimentally. The simulations reproduce the conformation transitions observed by NMR and suggest that proposed differences between the crystal structure and the solution structure are an artifact of the way the NMR data has been interpreted in terms of a structural model. The spontaneous formation of both back-to-back and face-to-face dimers was observed in the simulations. This has allowed a detailed analysis of the origin of the cooperatively between ligand binding and dimerization and suggests that the formation of face-to-face dimers could be functionally significant. The work also highlights the possible role of structural water in stabilizing the vancomycin ligand complex and its role in the manifestation of vancomycin resistance.

Disturb or Stabilize? A Molecular Dynamics Study of the Effects of Resorcinolic Lipids on Phospholipid Bilayers

Publisher: Elsevier BV

Date: 04-2009

DOI: 10.1016/J.BPJ.2009.01.040

Lipid Bilayers: The Effect of Force Field on Ordering and Dynamics

Publisher: American Chemical Society (ACS)

Date: 18-10-2012

DOI: 10.1021/CT300675Z

Abstract: The sensitivity of the structure and dynamics of a fully hydrated pure bilayer of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in molecular dynamics simulations to changes in force-field and simulation parameters has been assessed. Three related force fields (the Gromos 54A7 force field, a Gromos 53A6-derived parameter set and a variant of the Berger parameters) in combination with either particle-mesh Ewald (PME) or a reaction field (RF) were compared. Structural properties such as the area per lipid, carbon-deuterium order parameters, electron density profile and bilayer thicknesses, are reproduced by all the parameter sets within the uncertainty of the available experimental data. However, there are clear differences in the ordering of the glycerol backbone and choline headgroup, and the orientation of the headgroup dipole. In some cases, the degree of ordering was reminiscent of a liquid-ordered phase. It is also shown that, although the lateral diffusion of the lipids in the plane of the bilayer is often used to validate lipid force fields, because of the uncertainty in the experimental measurements and the fact that the lateral diffusion is dependent on the choice of the simulation conditions, it should not be employed as a measure of quality. Finally, the simulations show that the effect of small changes in force-field parameters on the structure and dynamics of a bilayer is more significant than the treatment of the long-range electrostatic interactions using RF or PME. Overall, the Gromos 54A7 best reproduced the range of experimental data examined.

The effect of membrane curvature on the conformation of antimicrobial peptides: implications for binding and the mechanism of action

Publisher: Springer Science and Business Media LLC

Date: 26-01-2011

DOI: 10.1007/S00249-011-0677-4

Molecular dynamics simulation of the spontaneous formation of a small DPPC vesicle in water in atomistic detail

Publisher: American Chemical Society (ACS)

Date: 20-03-2004

DOI: 10.1021/JA0398417

Abstract: Molecular dynamics simulations have been used to study the spontaneous aggregation of a concentrated solution of dipalmitoylphosphatidylcholine (DPPC) molecules in water into a small vesicle. The molecules were represented in atomistic detail. Starting from a DPPC solution in water, an oblong vesicle with a long axis of 15 nm and short axes of 10 nm was formed spontaneously. After 90 ns of simulation, the vesicle contained a number of water pores. Water pores were shown to facilitate exchange of lipids between inner and outer leaflets. Lipid tails were shown to be less ordered in the inner leaflet of the vesicle, as compared to those in the outer leaflet of the vesicle and an equilibrated lamellar bilayer.

Molecular dynamics simulations of the hydrophobin SC3 at a hydrophobic/hydrophilic interface

Publisher: Wiley

Date: 12-06-2006

DOI: 10.1002/PROT.20936

Abstract: Hydrophobins are small ( approximately 100 aa) proteins that have an important role in the growth and development of mycelial fungi. They are surface active and, after secretion by the fungi, self-assemble into hipathic membranes at hydrophobic/hydrophilic interfaces, reversing the hydrophobicity of the surface. In this study, molecular dynamics simulation techniques have been used to model the process by which a specific class I hydrophobin, SC3, binds to a range of hydrophobic/hydrophilic interfaces. The structure of SC3 used in this investigation was modeled based on the crystal structure of the class II hydrophobin HFBII using the assumption that the disulfide pairings of the eight conserved cysteine residues are maintained. The proposed model for SC3 in aqueous solution is compact and globular containing primarily beta-strand and coil structures. The behavior of this model of SC3 was investigated at an air/water, an oil/water, and a hydrophobic solid/water interface. It was found that SC3 preferentially binds to the interfaces via the loop region between the third and fourth cysteine residues and that binding is associated with an increase in alpha-helix formation in qualitative agreement with experiment. Based on a combination of the available experiment data and the current simulation studies, we propose a possible model for SC3 self-assembly on a hydrophobic solid/water interface.

Structural Characterization of Two Metastable ATP-Bound States of P-Glycoprotein

Publisher: Public Library of Science (PLoS)

Date: 14-03-2014

DOI: 10.1371/JOURNAL.PONE.0091916

Molecular dynamics simulation of the formation, structure, and dynamics of small phospholipid vesicles

Publisher: American Chemical Society (ACS)

Date: 13-11-2003

DOI: 10.1021/JA0352092

Abstract: Here, we use coarse grained molecular dynamics (MD) simulations to study the spontaneous aggregation of dipalmitoylphosphatidylcholine (DPPC) lipids into small unilamellar vesicles. We show that the aggregation process occurs on a nanosecond time scale, with bicelles and cuplike vesicles formed at intermediate stages. Formation of hemifused vesicles is also observed at higher lipid concentration. With either 25% dipalmitoylphosphatidylethanolamine (DPPE) or lysoPC mixed into the system, the final stages of the aggregation process occur significantly faster. The structure of the spontaneously formed vesicles is analyzed in detail. Microsecond simulations of isolated vesicles reveal significant differences in the packing of the lipids between the inner and outer monolayers, and between PC, PE, and lysoPC. Due to the small size of the vesicles they remain almost perfectly spherical, undergoing very limited shape fluctuations or bilayer undulations. The lipid lateral diffusion rate is found to be faster in the outer than in the inner monolayer. The water permeability coefficient of the pure DPPC vesicles is of the order of 10(-)(3) cm s(-)(1), in agreement with experimental measurements.

The effect of box shape on the dynamic properties of proteins simulated under periodic boundary conditions

Publisher: Wiley

Date: 15-12-2006

DOI: 10.1002/JCC.20341

Abstract: The effect of the box shape on the dynamic behavior of proteins simulated under periodic boundary conditions is evaluated. In particular, the influence of simulation boxes defined by the near-densest lattice packing (NDLP) in conjunction with rotational constraints is compared to that of standard box types without these constraints. Three different proteins of varying size, shape, and secondary structure content were examined in the study. The statistical significance of differences in RMSD, radius of gyration, solvent-accessible surface, number of hydrogen bonds, and secondary structure content between proteins, box types, and the application or not of rotational constraints has been assessed. Furthermore, the differences in the collective modes for each protein between different boxes and the application or not of rotational constraints have been examined. In total 105 simulations were performed, and the results compared using a three-way multivariate analysis of variance (MANOVA) for properties derived from the trajectories and a three-way univariate analysis of variance (ANOVA) for collective modes. It is shown that application of roto-translational constraints does not have a statistically significant effect on the results obtained from the different simulations. However, the choice of simulation box was found to have a small (5-10%), but statistically significant effect on the behavior of two of the three proteins included in the study.

A New Force Field for Simulating Phosphatidylcholine Bilayers

Publisher: Wiley

Date: 13-10-2010

DOI: 10.1002/JCC.21396

Abstract: A new force field for the simulation of dipalmitoylphosphatidylcholine (DPPC) in the liquid-crystalline, fluid phase at zero surface tension is presented. The structure of the bilayer with the area per lipid (0.629 nm(2) experiment 0.629-0.64 nm(2)), the volume per lipid (1.226 nm(3) experiment 1.229-1.232 nm(3)), and the ordering of the palmitoyl chains (order parameters) are all in very good agreement with experiment. Experimental electron density profiles are well reproduced in particular with regard to the penetration of water into the bilayer. The force field was further validated by simulating the spontaneous assembly of DPPC into a bilayer in water. Notably, the timescale on which membrane sealing was observed using this model appears closer to the timescales for membrane resealing suggested by electroporation experiments than previous simulations using existing models.

Could Cardiolipin Protect Membranes against the Action of Certain Antimicrobial Peptides? Aurein 1.2, a Case Study

Publisher: American Chemical Society (ACS)

Date: 03-12-2018

DOI: 10.1021/ACSOMEGA.8B02710

The structure of a two-disulfide intermediate assists in elucidating the oxidative folding pathway of a cyclic cystine knot protein

Publisher: Elsevier BV

Date: 06-2008

DOI: 10.1016/J.STR.2008.02.023

Abstract: We have determined the three-dimensional structure of a two-disulfide intermediate (Cys(8)-Cys(20), Cys(14)-Cys(26)) on the oxidative folding pathway of the cyclotide MCoTI-II. Cyclotides have a range of bioactivities and, because of their exceptional stability, have been proposed as potential molecular scaffolds for drug design applications. The three-dimensional structure of the stable two-disulfide intermediate shows for the most part identical secondary and tertiary structure to the native state. The only exception is a flexible loop, which is collapsed onto the protein core in the native state, whereas in the intermediate it is more loosely associated with the remainder of the protein. The results suggest that the native fold of the peptide does not represent the free energy minimum in the absence of the Cys(1)-Cys(18) disulfide bridge and that although there is not a large energy barrier, the peptide must transiently adopt an energetically unfavorable state before the final disulfide can form.

Binding and Enantiomeric Selectivity of Threonyl-tRNA Synthetase

Publisher: American Chemical Society (ACS)

Date: 27-02-2009

DOI: 10.1021/JA9002124

Abstract: A combination of MD simulations and free energy calculations have been used to propose a new model for the binding of amino acids to threonyl-tRNA-synthetase which not only yields a stable binding mode for l-Ser but also can explain the mechanism by which the editing domains of aminoacyl-tRNA-synthetases are enantiomeric selective preferentially binding d-amino acids.

Inclusion of ionization states of ligands in affinity calculations

Publisher: Wiley

Date: 16-12-2009

DOI: 10.1002/PROT.22326

Abstract: When estimating binding affinities of a ligand, which can exists in multiple forms, for a target molecule, one must consider all possible competing equilibria. Here, a method is presented that estimates the contribution of the protonation equilibria of a ligand in solution to the measured or calculated binding affinity. The method yields a correction to binding constants that are based on the total concentration of inhibitor (the sum of all ionized forms of the inhibitor in solution) to account for the complexed form of the inhibitor only. The method is applied to the calculation of the difference in binding affinity of two inhibitors, 2-phosphoglycolate (PGA) and its phoshonate analog 3-phosphonopropionate (3PP), for the glycolytic enzyme triosephosphate isomerase. Both inhibitors have three titrating sites and exist in solution as a mixture of different forms. In this case the form that actually binds to the enzyme is present at relative low concentrations. The contributions of the alternative forms to the difference in binding energies is estimated by means of molecular dynamics simulations and corrections. The inhibitors undergo a pK(a) shift upon binding that is estimated by ab initio calculations. An interesting finding is that the affinity difference of the two inhibitors is not due to different interactions in the active site of the enzyme, but rather due to the difference in the solvation properties of the inhibitors.

Small-Angle X-Ray Scattering for the Discerning Macromolecular Crystallographer

Publisher: CSIRO Publishing

Date: 2014

DOI: 10.1071/CH14396

Abstract: The role of small-angle X-ray scattering (SAXS) in structural biology is now well established, and its usefulness in combination with macromolecular crystallography is clear. However, the highly averaged SAXS data present a significant risk of over-interpretation to the unwary practitioner, and it can be challenging to frame SAXS results in a manner that maximises the reliability of the conclusions drawn. In this review, a series of recent ex les are used to illustrate both the challenges for interpretation and approaches through which these can be overcome.

Entropy calculations on the molten globule state of a protein: Side-chain entropies of alpha-lactalbumin

Publisher: Wiley

Date: 06-12-2002

DOI: 10.1002/PROT.1166

Abstract: We present entropy estimates based on molecular dynamics simulations of models of the molten globule state of the protein alpha-lactalbumin at low pH. The entropy calculations use the covariance matrix of atom-positional fluctuations and yield the complete configurational entropy. The configurational entropy of the entire protein and of each of its side chains is calculated. Exposed side chains show a larger entropy compared to buried side chains. A comparison to data from rotamer counting is made and significant differences are found.

Validating lipid force fields against experimental data: Progress, challenges and perspectives

Publisher: Elsevier BV

Date: 07-2016

DOI: 10.1016/J.BBAMEM.2016.01.029

Abstract: Biological membranes display a great ersity in lipid composition and lateral structure that is crucial in a variety of cellular functions. Simulations of membranes have contributed significantly to the understanding of the properties, functions and behaviour of membranes and membrane-protein assemblies. This success relies on the ability of the force field used to describe lipid-lipid and lipid-environment interactions accurately, reproducibly and realistically. In this review, we present some recent progress in lipid force-field development and validation strategies. In particular, we highlight how a range of properties obtained from various experimental techniques on lipid bilayers and membranes, can be used to assess the quality of a force field. We discuss the limitations and assumptions that are inherent to both computational and experimental approaches and how these can influence the comparison between simulations and experimental data. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.

Multiple-choice knapsack for assigning partial atomic charges in drug-like molecules

Publisher: Schloss Dagstuhl - Leibniz-Zentrum fuer Informatik GmbH, Wadern/Saarbruecken, Germany

Date: 2018

DOI: 10.4230/LIPICS.WABI.2018.16

THE BINDING OF AN INDEFINITELY ASSOCIATING LIGAND TO ACCEPTOR - CONSIDERATION OF MONO-VALENT LIGAND SPECIES BINDING TO A MULTIVALENT ACCEPTOR

Publisher: Elsevier BV

Date: 03-1988

DOI: 10.1016/S0022-5193(88)80231-5

Abstract: Currently available binding theory is extended to incorporate the concept of indefinite self-association of the ligand. Binding equations are formulated in closed form for the case of the binding to a multivalent acceptor of a ligand capable of isodesmically indefinitely self-associating in a "head-to-tail" mode such that each ligand state bears one site capable of interacting with the acceptor. It is shown both mathematically and by way of numerical ex le that this system will give rise exclusively to binding curves convex to the r-axis in Scatchard format. Thus, the system provides another ex le of a binding mechanism capable of generating an apparent negatively co-operative binding response.

Binding of Starch Fragments to the Starch Branching Enzyme: Implications for Developing Slower-Digesting Starch

Publisher: American Chemical Society (ACS)

Date: 09-07-2015

DOI: 10.1021/ACS.BIOMAC.5B00710

Abstract: Molecular weight distributions of starch branches affect functional properties, which can be controlled by engineering starch branching enzymes (SBEs). Molecular dynamics and docking approaches are used to examine interactions between SBE and starch fragments. In the native protein, three residues formed stable interactions with starch fragments in the central binding region these residues may play key roles in substrate recognition. Fragments containing 5-12 glucose units interacted more tightly with SBE than smaller fragments, suggesting a minimal functional fragment size of 5, agreeing with experiment. Effects of three different point mutations on interactions with maltopentaose in the central binding region correlated well with experiment. Simulations indicate that SBE may template formation of the crystalline lamellae characteristic of native starch, consistent with the observation that crystalline lamellae formed by starch in a plant, are not necessarily the state of lowest free energy. The methodology will help develop starches with optimized functional properties.

Optimization of Empirical Force Fields by Parameter Space Mapping: A Single-Step Perturbation Approach

Publisher: American Chemical Society (ACS)

Date: 21-11-2017

DOI: 10.1021/ACS.JCTC.7B00800

Abstract: A general method for parametrizing atomic interaction functions is presented. The method is based on an analysis of surfaces corresponding to the difference between calculated and target data as a function of alternative combinations of parameters (parameter space mapping). The consideration of surfaces in parameter space as opposed to local values or gradients leads to a better understanding of the relationships between the parameters being optimized and a given set of target data. This in turn enables for a range of target data from multiple molecules to be combined in a robust manner and for the optimal region of parameter space to be trivially identified. The effectiveness of the approach is illustrated by using the method to refine the chlorine 6-12 Lennard-Jones parameters against experimental solvation free enthalpies in water and hexane as well as the density and heat of vaporization of the liquid at atmospheric pressure for a set of 10 aromatic-chloro compounds simultaneously. Single-step perturbation is used to efficiently calculate solvation free enthalpies for a wide range of parameter combinations. The capacity of this approach to parametrize accurate and transferrable force fields is discussed.

DECOMPOSITION OF THE FREE-ENERGY OF A SYSTEM IN TERMS OF SPECIFIC INTERACTIONS - IMPLICATIONS FOR THEORETICAL AND EXPERIMENTAL STUDIES

Publisher: Elsevier BV

Date: 07-1994

DOI: 10.1006/JMBI.1994.1430

Abstract: Recently, a number of methods have been proposed that are designed to extract contributions to the change in free energy associated with a given perturbation or mutation of a protein originating from specific residue-residue or atom-atom interactions, both based on theoretical calculations and on experimental data. We caution here that detailed analysis based on these methods is unreliable. It is demonstrated, both from first principles using statistical mechanics and by way of ex le, that in a general case a meaningful decomposition of the free energy in terms of specific residue-residue or atom-atom interactions is not possible.

Effect of Poly(ethylene glycol) (PEG) Spacers on the Conformational Properties of Small Peptides: A Molecular Dynamics Study

Publisher: American Chemical Society (ACS)

Date: 12-2010

DOI: 10.1021/LA103800H

Abstract: Poly(ethylene glycol) (PEG) is used as an inert spacer in a wide range of biotechnological applications such as to display peptides and proteins on surfaces for diagnostic purposes. In such applications it is critical that the peptide is accessible to solvent and that the PEG does not affect the conformational properties of the peptide to which it is attached. Using molecular dynamics (MD) simulation techniques, we have investigated the influence of a commonly used PEG spacer on the conformation properties of a series of five peptides with differing physical-chemical properties (YGSLPQ, VFVVFV, GSGGSG, EEGEEG, and KKGKKG). The conformational properties of the peptides were compared (a) free in solution, (b) attached to a PEG-11 spacer in solution, and (c) constrained to a two-dimensional lattice via a (PEG-11)(3) spacer, mimicking a peptide displayed on a surface as used in microarray techniques. The simulations suggest that the PEG spacer has little effect on the conformational properties of small neutral peptides but has a significant effect on the conformational properties of small highly charged peptides. When constrained to a two-dimensional surface at peptide densities similar to those used experimentally, it was found that the peptides, in particular the polar and nonpolar peptides, aggregated strongly. The peptides also partitioned into the PEG layer. Potentially, this means that at high packing densities only a small fraction of the peptide attached to the surface would in fact be accessible to a potential interaction partner.

Understanding the Activated Form of a Class-I Fusion Protein: Modeling the Interaction of the Ebola Virus Glycoprotein 2 with a Lipid Bilayer

Publisher: American Chemical Society (ACS)

Date: 22-09-2020

DOI: 10.1021/ACS.BIOCHEM.0C00527

SIMULATION OF THE THERMAL-DENATURATION OF HEN EGG-WHITE LYSOZYME - TRAPPING THE MOLTEN GLOBULE STATE

Publisher: American Chemical Society (ACS)

Date: 09-1992

DOI: 10.1021/BI00149A001

Abstract: In the study of protein folding, much attention has focused on the characterization of folding intermediates. We report here molecular dynamics simulations in which the initial stages of the thermal denaturation of hen egg white lysozyme in aqueous solution are examined in detail. It is found that lysozyme unfolds in a two-stage process with the initial formation a quasi-stable state in which significant rearrangement of the secondary structure takes place. No evidence for distinct folding domains was found. The simulations suggest that the formation of well-defined secondary structure occurs after the initial collapse of the peptide chain and thus tend against the framework model of protein folding.

Effect of Triclosan and Chloroxylenol on Bacterial Membranes

Publisher: American Chemical Society (ACS)

Date: 04-06-2019

DOI: 10.1021/ACS.JPCB.9B02588

Abstract: Triclosan and chloroxylenol are broad-spectrum biocides used extensively in healthcare and consumer products. They have been suggested to perturb the structure of bacterial membranes, but studies so far have not considered that most bacterial membranes contain large amounts of branched-chain lipids. Here, molecular dynamics simulation is used to examine the effect of the two biocides on membranes consisting of lipids with methyl-branched chains, cyclopropanated chains, and nonbranched chains. It is shown that triclosan and chloroxylenol induced a phase transition in membranes from a liquid-crystalline to a liquid-ordered phase irrespective of the presence and nature of branching groups. At high concentration, chloroxylenol promoted chain interdigitation. Our results suggest that triclosan and chloroxylenol decrease the degree of fluidity of membranes and that this effect is more pronounced in bacterial membranes. As a result, their biocidal activity could be associated with a change in the function of membrane proteins.

Validation of ligands in X-ray crystal structures

Publisher: Informa UK Limited

Date: 18-05-2015

DOI: 10.1080/07391102.2015.1032816

Weak, Strong, And Coherent Regimes Of Frohlich Condensation And Their Applications To Terahertz Medicine And Quantum Consciousness

Publisher: Proceedings of the National Academy of Sciences

Date: 17-03-2009

DOI: 10.1073/PNAS.0806273106

Abstract: In 1968, Fröhlich showed that a driven set of oscillators can condense with nearly all of the supplied energy activating the vibrational mode of lowest frequency. This is a remarkable property usually compared with Bose–Einstein condensation, superconductivity, lasing, and other unique phenomena involving macroscopic quantum coherence. However, despite intense research, no unambiguous ex le has been documented. We determine the most likely experimental signatures of Fröhlich condensation and show that they are significant features remote from the extraordinary properties normally envisaged. Fröhlich condensates are classified into 3 types: weak condensates in which profound effects on chemical kinetics are possible, strong condensates in which an extremely large amount of energy is channeled into 1 vibrational mode, and coherent condensates in which this energy is placed in a single quantum state. Coherent condensates are shown to involve extremely large energies, to not be produced by the Wu–Austin dynamical Hamiltonian that provides the simplest depiction of Fröhlich condensates formed using mechanically supplied energy, and to be extremely fragile. They are inaccessible in a biological environment. Hence the Penrose–Hameroff orchestrated objective-reduction model and related theories for cognitive function that embody coherent Fröhlich condensation as an essential element are untenable. Weak condensates, however, may have profound effects on chemical and enzyme kinetics, and may be produced from biochemical energy or from radio frequency, microwave, or terahertz radiation. Pokorný's observed 8.085-MHz microtubulin resonance is identified as a possible candidate, with microwave reactors (green chemistry) and terahertz medicine appearing as other feasible sources.

A ring to rule them all: the effect of cyclopropane Fatty acids on the fluidity of lipid bilayers.

Publisher: American Chemical Society (ACS)

Date: 16-04-2015

DOI: 10.1021/ACS.JPCB.5B00958

Abstract: Cyclopropane fatty acids are widespread in bacteria. As their concentration increases on exposure to hostile environments, they have been proposed to protect membranes. Here, the effect of cyclopropane and unsaturated fatty acids, both in cis and trans configurations, on the packing, order, and fluidity of lipid bilayers is explored using molecular dynamics simulations. It is shown that cyclopropane fatty acids disrupt lipid packing, favor the occurrence of gauche defects in the chains, and increase the lipid lateral diffusion, suggesting that they enhance fluidity. At the same time, they generally induce a greater degree of order than unsaturated fatty acids of the same configuration and limit the rotation about the bonds surrounding the cyclopropane ring. This indicates that cyclopropane fatty acids may fulfill a dual function: stabilizing membranes against adverse conditions while simultaneously promoting their fluidity. Marked differences in the effect of cis- and trans-monocyclopropanated fatty acids were also observed, suggesting that they may play alternative roles in membranes.

Wilfred van Gunsteren: 35 Years of Biomolecular Simulation

Publisher: American Chemical Society (ACS)

Date: 09-10-2012

DOI: 10.1021/CT300692S

Mimicking the action of folding chaperones by Hamiltonian replica-exchange molecular dynamics simulations: Application in the refinement of de novo models

Publisher: Wiley

Date: 13-04-2012

DOI: 10.1002/PROT.24068

Abstract: The efficiency of using a variant of Hamiltonian replica-exchange molecular dynamics (Chaperone H-replica-exchange molecular dynamics [CH-REMD]) for the refinement of protein structural models generated de novo is investigated. In CH-REMD, the interaction between the protein and its environment, specifically, the electrostatic interaction between the protein and the solvating water, is varied leading to cycles of partial unfolding and refolding mimicking some aspects of folding chaperones. In 10 of the 15 cases examined, the CH-REMD approach s led structures in which the root-mean-square deviation (RMSD) of secondary structure elements (SSE-RMSD) with respect to the experimental structure was more than 1.0 Å lower than the initial de novo model. In 14 of the 15 cases, the improvement was more than 0.5 Å. The ability of three different statistical potentials to identify near-native conformations was also examined. Little correlation between the SSE-RMSD of the s led structures with respect to the experimental structure and any of the scoring functions tested was found. The most effective scoring function tested was the DFIRE potential. Using the DFIRE potential, the SSE-RMSD of the best scoring structures was on average 0.3 Å lower than the initial model. Overall the work demonstrates that targeted enhanced-s ling techniques such as CH-REMD can lead to the systematic refinement of protein structural models generated de novo but that improved potentials for the identification of near-native structures are still needed.

Understanding the performance differences between solution and vacuum deposited OLEDs: A computational approach

Publisher: AIP Publishing

Date: 06-2022

DOI: 10.1063/5.0091142

Abstract: Solution-processing of organic light-emitting diode films has potential advantages in terms of cost and scalability over vacuum-deposition for large area applications. However, solution processed small molecule films can have lower overall device performance. Here, novel molecular dynamics techniques are developed to enable faster simulation of solvent evaporation that occurs during solution processing and give films of thicknesses relevant to real devices. All-atom molecular dynamics simulations are then used in combination with kinetic Monte Carlo transport modeling to examine how differences in morphology stemming from solution or vacuum film deposition affect charge transport and exciton dynamics in films consisting of light-emitting bis(2-phenylpyridine)(acetylacetonate)iridium(III) [Ir(ppy)2(acac)] guest molecules in a 4,4′-bis(N-carbazolyl)biphenyl host. While the structures of the films deposited from vacuum and solution were found to differ, critically, only minor variations in the transport properties were predicted by the simulations even if trapped solvent was present.

Coarse grained model for semiquantitative lipid simulations

Publisher: American Chemical Society (ACS)

Date: 02-12-2004

DOI: 10.1021/JP036508G

Factors That Affect the Degree of Twist in beta-Sheet Structures: A Molecular Dynamics Simulation Study of a Cross-beta Filament of the GNNQQNY Peptide (vol 113, pg 1728, 2009)

Publisher: American Chemical Society (ACS)

Date: 06-07-2009

DOI: 10.1021/JP905822D

Revisiting the scissor-like mechanism of activation for the erythropoietin receptor

Publisher: Wiley

Date: 18-08-2016

DOI: 10.1002/1873-3468.12340

Abstract: An interpretation of alternative crystal structures of the erythropoietin receptor, with and without ligand, led to the proposal of a scissor-like mechanism of activation. This model has been propagated in the literature and is still being used to interpret crystal structures of related type-I cytokine receptors. Here, we assess whether the model remains compatible with current knowledge on the family of type-I cytokine receptors, and consider whether the model, as initially presented, is truly supported by the crystal structures on which it was originally based.

Challenges in the determination of the binding modes of non-standard ligands in X-ray crystal complexes

Publisher: Springer Science and Business Media LLC

Date: 04-11-2011

DOI: 10.1007/S10822-010-9397-6

Abstract: Despite its central role in structure based drug design the determination of the binding mode (position, orientation and conformation in addition to protonation and tautomeric states) of small heteromolecular ligands in protein:ligand complexes based on medium resolution X-ray diffraction data is highly challenging. In this perspective we demonstrate how a combination of molecular dynamics simulations and free energy (FE) calculations can be used to correct and identify thermodynamically stable binding modes of ligands in X-ray crystal complexes. The consequences of inappropriate ligand structure, force field and the absence of electrostatics during X-ray refinement are highlighted. The implications of such uncertainties and errors for the validation of virtual screening and fragment-based drug design based on high throughput X-ray crystallography are discussed with possible solutions and guidelines.

Editorial overview: Theory and simulation: Progress, yes; revolutions, no

Publisher: Elsevier BV

Date: 04-2020

DOI: 10.1016/J.SBI.2020.02.001

OFraMP: a fragment-based tool to facilitate the parametrization of large molecules

Publisher: Springer Science and Business Media LLC

Date: 13-06-2023

DOI: 10.1007/S10822-023-00511-7

Abstract: An Online tool for Fragment-based Molecule Parametrization (OFraMP) is described. OFraMP is a web application for assigning atomic interaction parameters to large molecules by matching sub-fragments within the target molecule to equivalent sub-fragments within the Automated Topology Builder (ATB, atb.uq.edu.au) database. OFraMP identifies and compares alternative molecular fragments from the ATB database, which contains over 890,000 pre-parameterized molecules, using a novel hierarchical matching procedure. Atoms are considered within the context of an extended local environment (buffer region) with the degree of similarity between an atom in the target molecule and that in the proposed match controlled by varying the size of the buffer region. Adjacent matching atoms are combined into progressively larger matched sub-structures. The user then selects the most appropriate match. OFraMP also allows users to manually alter interaction parameters and automates the submission of missing substructures to the ATB in order to generate parameters for atoms in environments not represented in the existing database. The utility of OFraMP is illustrated using the anti-cancer agent paclitaxel and a dendrimer used in organic semiconductor devices. Graphical abstract OFraMP applied to paclitaxel (ATB ID 35922).

Effect of Binding on Enantioselectivity of Epoxide Hydrolase

Publisher: American Chemical Society (ACS)

Date: 09-02-2018

DOI: 10.1021/ACS.JCIM.7B00353

Abstract: Molecular dynamics simulations and free energy calculations have been used to investigate the effect of ligand binding on the enantioselectivity of an epoxide hydrolase (EH) from Aspergillus niger. Despite sharing a common mechanism, a wide range of alternative mechanisms have been proposed to explain the origin of enantiomeric selectivity in EHs. By comparing the interactions of ( R)- and ( S)-glycidyl phenyl ether (GPE) with both the wild type (WT, E = 3) and a mutant showing enhanced enantioselectivity to GPE (LW202, E = 193), we have examined whether enantioselectivity is due to differences in the binding pose, the affinity for the ( R)- or ( S)- enantiomers, or a kinetic effect. The two enantiomers were easily accommodated within the binding pockets of the WT enzyme and LW202. Free energy calculations suggested that neither enzyme had a preference for a given enantiomer. The two substrates s led a wide variety of conformations in the simulations with the sterically hindered and unhindered carbon atoms of the GPE epoxide ring both coming in close proximity to the nucleophilic aspartic acid residue. This suggests that alternative pathways could lead to the formation of a ( S)- and ( R)-diol product. Together, the calculations suggest that the enantioselectivity is due to kinetic rather than thermodynamic effects and that the assumption that one substrate results in one product when interpreting the available experimental data and deriving E-values may be inappropriate in the case of EHs.

A new 2,2,2-trifluoroethanol model for molecular dynamics simulations

Publisher: American Chemical Society (ACS)

Date: 12-2000

DOI: 10.1021/JP002115V

A molecular dynamics study of the structural stability of HIV-1 protease under physiological conditions: The role of Na+ ions in stabilizing the active site

Publisher: Wiley

Date: 23-11-2005

DOI: 10.1002/PROT.20304

Abstract: HIV-1 protease is most active under weakly acidic conditions (pH 3.5-6.5), when the catalytic Asp25 and Asp25' residues share 1 proton. At neutral pH, this proton is lost and the stability of the structure is reduced. Here we present an investigation of the effect of pH on the dynamics of HIV-1 protease using MD simulation techniques. MD simulations of the solvated HIV-1 protease with the Asp25/25' residues monoprotonated and deprotonated have been performed. In addition we investigated the effect of the inclusion of Na(+) and Cl(-) ions to mimic physiological salt conditions. The simulations of the monoprotonated form and deprotonated form including Na(+) show very similar behavior. In both cases the protein remained stable in the compact, "self-blocked" conformation in which the active site is blocked by the tips of the flaps. In the deprotonated system a Na(+) ion binds tightly to the catalytic dyad shielding the repulsion between the COO(-) groups. Ab initio calculations also suggest the geometry of the active site with the Na(+) bound closely resembles that of the monoprotonated case. In the simulations of the deprotonated form (without Na(+) ions), a water molecule bound between the Asp25 Asp25' side-chains. This disrupted the dimerization interface and eventually led to a fully open conformation.

Curved or linear? Predicting the 3‐dimensional structure of α‐helical antimicrobial peptides in an amphipathic environment

Publisher: Wiley

Date: 17-12-2020

DOI: 10.1002/1873-3468.13705

Abstract: α-Helical membrane-active antimicrobial peptides (AMPs) are known to act via a range of mechanisms, including the formation of barrel-stave and toroidal pores and the micellisation of the membrane (carpet mechanism). Different mechanisms imply that the peptides adopt different 3D structures when bound at the water-membrane interface, a highly hipathic environment. Here, an evolutionary algorithm is used to predict the 3D structure of a range of α-helical membrane-active AMPs at the water-membrane interface by optimising hipathicity. This hipathic structure prediction (ASP) is capable of distinguishing between curved and linear peptides solved experimentally, potentially allowing the activity and mechanism of action of different membrane-active AMPs to be predicted. The ASP algorithm is accessible via a web interface at atb.uq.edu.au/asp/.

Conformational polymorphism of the PrP106-126 peptide in different environments: A molecular dynamics study

Publisher: American Chemical Society (ACS)

Date: 2006

DOI: 10.1021/JP052722O

Abstract: Extensive molecular dynamic simulations (approximately 240 ns) have been used to investigate the conformational behavior of PrP106-126 prion peptide in four different environments (water, dimethyl sulfoxide, hexane, and trifluoroethanol) and under both neutral and acidic conditions. The conformational polymorphism of PrP106-126 in solution observed in the simulations supports the role of this fragment in the structural transition of the native to the abnormal form of prion protein in response to changes in the local environmental conditions. The peptide in solution is primarily unstructured. The simulations show an increased presence of helical structure in an apolar solvent, in agreement with the results from circular dichroism spectroscopy. In water solution, beta-sheet elements were observed between residues 108-112 and either residues 115-121 or 121-126. An alpha-beta transition was observed under neutral conditions. In DMSO, the peptide adopted an extended conformation, in agreement with nuclear magnetic resonance experiments.

Molecular Dynamics Simulations of the Interactions of DMSO with DPPC and DOPC Phospholipid Membranes

Publisher: American Chemical Society (ACS)

Date: 20-09-2012

DOI: 10.1021/JP3035538

Abstract: Molecular dynamics simulations have been used to investigate the effect of DMSO on 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) phospholipid bilayers. The concentration of DMSO was varied between 0 and 25.0 mol %. For both lipids, DMSO causes the membrane to expand in the plane of the membrane while thinning normal to that plane. Above a critical concentration, pores in the membrane form spontaneously, and if the concentration is increased further, then the bilayer structure is destroyed. Even at concentrations below those required to induce pores, DMSO readily diffuses across the bilayers. The free-energy profile associated with the diffusion of a DMSO molecules across the membrane has been calculated. The simulations suggest that the DOPC bilayer is more resistant to the deleterious effects of DMSO, both increasing the stability of the membranes and decreasing the rate at which DMSO diffuses across the membrane. In this way, the work highlights the importance of investigating the lipid composition of cell membranes when characterizing the effects of cryosolvents.

The effect of the neglect of electronic polarization in peptide folding simulations

Publisher: American Chemical Society (ACS)

Date: 09-11-2002

DOI: 10.1021/JP026526I

The influence of trifluoromethyl groups on the miscibility of fluorinated alcohols with water: A molecular dynamics simulation study of 1,1,1-trifluoropropan-2-ol in aqueous solution

Publisher: American Chemical Society (ACS)

Date: 26-04-2003

DOI: 10.1021/JP026076U

Effect of Ring Size in omega-Alicyclic Fatty Acids on the Structural and Dynamical Properties Associated with Fluidity in Lipid Bilayers

Publisher: American Chemical Society (ACS)

Date: 14-10-2015

DOI: 10.1021/ACS.LANGMUIR.5B02635

Abstract: Fatty acids containing a terminal cyclic group such as cyclohexyl and cycloheptyl are commonly found in prokaryotic membranes, especially in those of thermo-acidophilic bacteria. These so-called ω-alicyclic fatty acids have been proposed to stabilize the membranes of bacteria by reducing the fluidity in membranes and increasing lipid packing and lipid chain order. In this article, molecular dynamics simulations are used to examine the effect of 3- to 7-membered cycloalkyl saturated and unsaturated (cyclopent-2-enyl and phenyl) rings in ω-alicyclic fatty acyl chains on the structure (lipid packing, lipid chain order, and fraction of gauche defects in the chains) and dynamics (lateral lipid diffusion) of a model lipid bilayer. It was found that ω-alicyclic chains in which the ring was saturated reduced lipid condensation and lowered chain order which would be associated with enhanced fluidity. However, this effect was limited. The lateral diffusion of the lipids diminished as the ring size increased. In particular, ω-cyclohexyl and ω-cycloheptyl acyl tails led to a decrease in lipid diffusion. In contrast, ω-alicyclic acyl chains that contain an unsaturated ring promoted membrane fluidity both in terms of changes in membrane structure and lipid diffusion. This may indicate that saturated and unsaturated terminal rings in ω-alicyclic fatty acids fulfill alternative functions within membranes. Overall, the simulations suggest that ω-alicyclic fatty acids in which the terminal ring is saturated might protect the membrane of thermo-acidophilic bacteria from high-temperature and low-pH conditions through a "dynamical barrier" that would limit lipid diffusion and transmembrane diffusion of undesired ions and molecules.

Model of 1,1,1,3,3,3-hexafluoro-propan-2-ol for molecular dynamics simulations

Publisher: American Chemical Society (ACS)

Date: 12-10-2001

DOI: 10.1021/JP012476Q

Folding and stability of the three-stranded beta-sheet peptide betanova: Insights from molecular dynamics simulations

Publisher: Wiley

Date: 30-01-2002

DOI: 10.1002/PROT.1175

Abstract: The dynamics of the three-stranded beta-sheet peptide Betanova has been studied at four different temperatures (280, 300, 350, and 450 K by molecular dynamics simulation techniques, in explicit water. Two 20-ns simulations at 280 K indicate that the peptide remains very flexible under "folding" conditions s ling a range of conformations that together satisfy the nuclear magnetic resonance (NMR)-derived experimental constraints. Two simulations at 300 K (above the experimental folding temperature) of 20 ns each show partial formation of "native"-like structure, which also satisfies most of the NOE constraints at 280 K. At higher temperature, the presence of compact states, in which a series of hydrophobic contacts remain present, are observed. This is consistent with experimental observations regarding the role of hydrophobic contacts in determining the peptide's stability and in initiating the formation of turns and loops. A set of different structures is shown to satisfy NMR-derived distance restraints and a possible mechanism for the folding of the peptide into the NMR-determined structure is proposed.

Free energy barrier estimation of unfolding the alpha-helical surfactant-associated polypeptide C

Publisher: Wiley

Date: 05-04-2001

DOI: 10.1002/PROT.1052

Abstract: Molecular dynamics simulations were conducted to estimate the free energy barrier of unfolding surfactant-associated polypeptide C (SP-C) from an alpha-helical conformation. Experimental studies indicate that while the helical fold of SP-C is thermodynamically stable in phospholipid micelles, it is metastable in a mixed organic solvent of CHCl3/CH3OH/0.1 M HCl at 32:64:5 (v/v/v), in which it undergoes an irreversible transformation to an insoluble aggregate that contains beta-sheet. On the basis of experimental observations, the free energy barrier was estimated to be approximately 100 kJ/mole by applying Eyring's transition state theory to the experimental rate of unfolding [Protein Sci 1998 :2533-2540]. These studies prompted us to carry out simulations to investigate the unwinding process of two helical turns encompassing residues 25-32 in water and in methanol. The results give an upper bound estimation for the free energy barrier of unfolding of SP-C of approximately 20 kJ/mole. The results suggest a need to reconsider the applicability of a single-mode activated process theory to protein unfolding.

On the Relative Merits of Equilibrium and Non-Equilibrium Simulations for the Estimation of Free-Energy Differences

Publisher: Wiley

Date: 15-11-2010

DOI: 10.1002/CPHC.201000562

Abstract: The possibility of estimating equilibrium free-energy profiles from multiple non-equilibrium simulations using the fluctuation-dissipation theory or the relation proposed by Jarzynski has attracted much attention. Although the Jarzynski estimator has poor convergence properties for simulations far from equilibrium, corrections have been derived for cases in which the work is Gaussian distributed. Here, we examine the utility of corrections proposed by Gore and collaborators using a simple dissipative system as a test case. The system consists of a single methane-like particle in explicit water. The Jarzynski equality is used to estimate the change in free energy associated with pulling the methane particle a distance of 3.9 nm at rates ranging from ~0.1 to 100 m s(-1). It is shown that although the corrections proposed by Gore and collaborators have excellent numerical performance, the profiles still converge slowly. Even when the corrections are applied in an ideal case where the work distribution is necessarily Gaussian, performing simulations under quasi-equilibrium conditions is still most efficient. Furthermore, it is shown that even for a single methane molecule in water, pulling rates as low as 1 m s(-1) can be problematic. The implications of this finding for studies in which small molecules or even large biomolecules are pulled through inhomogeneous environments at similar pulling rates are discussed.

The recognition of membrane-bound PtdIns3P by PX domains

Publisher: Wiley

Date: 12-05-2014

DOI: 10.1002/PROT.24593

Abstract: Phox-homology (PX) domains target proteins to the organelles of the secretary and endocytic systems by binding to phosphatidylinositol phospholipids (PIPs). Among all the structures of PX domains that have been solved, only three have been solved in a complex with the main physiological ligand: PtdIns3P. In this work, molecular dynamic simulations have been used to explore the structure and dynamics of the p40(phox) -PX domain and the SNX17-PX domain and their interaction with membrane-bound PtdIns3P. In the simulations, both PX domains associated spontaneously with the membrane-bound PtdIns3P and formed stable complexes. The interaction between the p40(phox) -PX domain and PtdIns3P in the membrane was found to be similar to the crystal structure of the p40(phox) -PX-PtdIns3P complex that is available. The interaction between the SNX17-PX domain and PtdIns3P was similar to that observed in the p40(phox) -PX-PtdIns3P complex however, some residues adopted different orientations. The simulations also showed that nonspecific interactions between the β1-β2 loop and the membrane play an important role in the interaction of membrane bound PtdIns3P and different PX domains. The behaviour of unbound PtdIns3P within a 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC) membrane environment was also examined and compared to the available experimental data and simulation studies of related molecules.

Elucidating the Spatial Arrangement of Emitter Molecules in Organic Light-Emitting Diode Films

Publisher: Wiley

Date: 07-02-2017

DOI: 10.1002/ANIE.201610727

Abstract: The effect of varying the emitter concentration on the structural properties of an archetypal phosphorescent blend consisting of 4,4'-bis(N-carbazolyl)biphenyl and tris(2-phenylpyridyl)iridium(III) has been investigated using non-equilibrium molecular dynamics (MD) simulations that mimic the process of vacuum deposition. By comparison with reflectometry measurements, we show that the simulations provide an accurate model of the average density of such films. The emitter molecules were found not to be evenly distributed throughout film, but rather they can form networks that provide charge and/or energy migration pathways, even at emitter concentrations as low as ≈5 weight percent. At slightly higher concentrations, percolated networks form that span the entire system. While such networks would give improved charge transport, they could also lead to more non-radiative pathways for the emissive state and a resultant loss of efficiency.

THE EFFECT OF ENVIRONMENT ON THE STABILITY OF AN INTEGRAL MEMBRANE HELIX - MOLECULAR-DYNAMICS SIMULATIONS OF SURFACTANT PROTEIN-C IN CHLOROFORM, METHANOL AND WATER

Publisher: Elsevier BV

Date: 04-1995

DOI: 10.1016/S0022-2836(05)80156-1

Abstract: A series of three molecular dynamics simulations at 300 K in explicit solvent environments of chloroform, methanol and water has been performed on the pulmonary surfactant lipoprotein, SP-C, comprising several consecutive valine residues in order to investigate the stability of the alpha-helical conformation. Two additional simulations were performed on truncated SP-C with a five-residue N-terminal deletion at 300 K and 500 K in water, the high temperature run in order to increase the rate of peptide denaturation. Indications of destabilization appear in chloroform during 1 ns while the SP-C alpha-helix is remarkably stable during 1 ns in methanol and water. In particular the polyvalyl part comprising residues Val15 to Val21 remains intact even at elevated temperature, and the valines do not disrupt the alpha-helical conformation. The valyl-rotamer s ling is partly restricted. Unfolding takes place successively along the primary sequence starting from the C-terminal end. Factors affecting polypeptide stability in molecular dynamics simulations are addressed. The intrinsic helix-forming tendency of valine residues and its dependence on the sequence context, and the role of the solvent environment in stabilizing or destabilizing an alpha-helical fold, are discussed.

Molecular dynamics simulations of mixed micelles modeling human bile

Publisher: American Chemical Society (ACS)

Date: 04-2002

DOI: 10.1021/BI015613I

Abstract: Extensive molecular dynamics (MD) simulations of binary systems of phospholipids and bile salts, a model for human bile, have been performed. Recent progress in hardware and software development allows simulation of the spontaneous aggregation of the constituents into small mixed micelles, in agreement with experimental observations. The MD simulations reveal the structure of these micelles at atomic detail. The phospholipids are packed radially with their headgroups at the surface and the hydrophobic tails pointing toward the micellar center. The bile salts act as wedges between the phospholipid headgroups, with their hydrophilic sides exposed to the aqueous environment. The structure of the micelles strongly resembles the previously proposed radial shell model. Simulations including small fractions of cholesterol reveal how cholesterol is solubilized inside these mixed micelles without changing their overall structure.

A potential new, stable state of the E-cadherin strand-swapped dimer in solution

Publisher: Springer Science and Business Media LLC

Date: 15-06-2018

DOI: 10.1007/S00249-017-1229-3

Abstract: E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution.

Monolayer ice

Publisher: American Physical Society (APS)

Date: 08-07-2003

DOI: 10.1103/PHYSREVLETT.91.025502

Charge Group Partitioning in Biomolecular Simulation

Publisher: Mary Ann Liebert Inc

Date: 03-2013

DOI: 10.1089/CMB.2012.0239

Automated Topology Builder Version 3.0: Prediction of Solvation Free Enthalpies in Water and Hexane

Publisher: American Chemical Society (ACS)

Date: 05-10-2018

DOI: 10.1021/ACS.JCTC.8B00768

Abstract: The ability of atomic interaction parameters generated using the Automated Topology Builder and Repository version 3.0 (ATB3.0) to predict experimental hydration free enthalpies (Δ G

Penrose-Hameroff Orchestrated Objective-Reduction Proposal For Human Consciousness Is Not Biologically Feasible

Publisher: American Physical Society (APS)

Date: 13-08-2009

DOI: 10.1103/PHYSREVE.80.021912

Feature Article Basic Ingredients of Free Energy Calculations: A Review

Publisher: Wiley

Date: 23-12-2010

DOI: 10.1002/JCC.21450

Abstract: Methods to compute free energy differences between different states of a molecular system are reviewed with the aim of identifying their basic ingredients and their utility when applied in practice to biomolecular systems. A free energy calculation is comprised of three basic components: (i) a suitable model or Hamiltonian, (ii) a s ling protocol with which one can generate a representative ensemble of molecular configurations, and (iii) an estimator of the free energy difference itself. Alternative s ling protocols can be distinguished according to whether one or more states are to be s led. In cases where only a single state is considered, six alternative techniques could be distinguished: (i) changing the dynamics, (ii) deforming the energy surface, (iii) extending the dimensionality, (iv) perturbing the forces, (v) reducing the number of degrees of freedom, and (vi) multi-copy approaches. In cases where multiple states are to be s led, the three primary techniques are staging, importance s ling, and adiabatic decoupling. Estimators of the free energy can be classified as global methods that either count the number of times a given state is s led or use energy differences. Or, they can be classified as local methods that either make use of the force or are based on transition probabilities. Finally, this overview of the available techniques and how they can be best used in a practical context is aimed at helping the reader choose the most appropriate combination of approaches for the biomolecular system, Hamiltonian and free energy difference of interest.

Protein a-Turns Recreated in Structurally Stable Small Molecules

Publisher: Wiley

Date: 29-09-2011

DOI: 10.1002/ANIE.201105119

Free Energy Perturbation Calculations

Publisher: Wiley

Date: 25-09-2002

DOI: 10.1002/0470845015.CFA010

The Cys3-Cys4 loop of the hydrophobin EAS is not required for rodlet formation and surface activity

Publisher: Elsevier BV

Date: 10-2008

DOI: 10.1016/J.JMB.2008.07.034

Abstract: Class I hydrophobins are fungal proteins that self-assemble into robust hipathic rodlet monolayers on the surface of aerial structures such as spores and fruiting bodies. These layers share many structural characteristics with amyloid fibrils and belong to the growing family of functional amyloid-like materials produced by microorganisms. Although the three-dimensional structure of the soluble monomeric form of a class I hydrophobin has been determined, little is known about the molecular structure of the rodlets or their assembly mechanism. Several models have been proposed, some of which suggest that the Cys3-Cys4 loop has a critical role in the initiation of assembly or in the polymeric structure. In order to provide insight into the relationship between hydrophobin sequence and rodlet assembly, we investigated the role of the Cys3-Cys4 loop in EAS, a class I hydrophobin from Neurospora crassa. Remarkably, deletion of up to 15 residues from this 25-residue loop does not impair rodlet formation or reduce the surface activity of the protein, and the physicochemical properties of rodlets formed by this mutant are indistinguishable from those of its full-length counterpart. In addition, the core structure of the truncation mutant is essentially unchanged. Molecular dynamics simulations carried out on the full-length protein and this truncation mutant binding to an air-water interface show that, although it is hydrophobic, the loop does not play a role in positioning the protein at the surface. These results demonstrate that the Cys3-Cys4 loop does not have an integral role in the formation or structure of the rodlets and that the major determinant of the unique properties of these proteins is the hipathic core structure, which is likely to be preserved in all hydrophobins despite the high degree of sequence variation across the family.

University Of Queensland

Location: Australia

View Organisation

University Of Sydney

Location: Australia

View Organisation

Force Fields For Structure Refinement And Computational Drug Design

Start Date: 2015

End Date: 2017

Funder: Australian Research Council

Elucidating The Morphology Of Organic Semiconductors At An Atomic Level

Start Date: 2020

End Date: 2021

Funder: Australian Research Council

Atomistic Simulations Of Lipid Vesicle Fusion

Start Date: 2004

End Date: 2007

Funder: Dutch Research Council

Modelling The Self-Organization Of Cell Membrane Components

Start Date: 2003

End Date: 2009

Funder: Dutch Research Council

Improving Empirical Force Fields: A Big-data Approach.

Start Date: 2018

End Date: 2020

Funder: Australian Research Council

Structure, Dynamics And Thermodynamics Of Self-organized Biomolecular Systems

Start Date: 2004

End Date: 2011

Funder: Dutch Research Council

Replica Exchange Method: Going Beyond The Current Limit Of Computer Protein Folding Experiments

Start Date: 2004

End Date: 2006

Funder: Dutch Research Council

A Computational Facility For Multi-scale Modelling In Bio And Nanotechnology

Start Date: 2008

End Date: 2008

Funder: Australian Research Council

Strengthening Merit-based Access And Support At The New National Computing Infrastructure Petascale Supercomputing Facility

Start Date: 2012

End Date: 2012

Funder: Australian Research Council

A New Paradigm For Class I Cytokine Receptor Activation

Start Date: 2015

End Date: 2018

Funder: National Health and Medical Research Council

Maintaining And Enhancing Merit-based Access To The NCI National Facility

Start Date: 2016

End Date: 2018

Funder: Australian Research Council

Sustaining And Strengthening Merit-based Access To National Computational Infrastructure

Start Date: 2019

End Date: 2021

Funder: Australian Research Council

Federation Fellowships - Grant ID: FF0455865

Start Date: 02-2005

End Date: 01-2010

Amount: $1,519,710.00

Funder: Australian Research Council

Linkage - International - Grant ID: LX0882184

Start Date: 2008

End Date: 04-2011

Amount: $31,675.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0878608

Start Date: 2008

End Date: 06-2011

Amount: $398,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP190100699

Start Date: 09-2020

End Date: 12-2022

Amount: $136,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0770375

Start Date: 2007

End Date: 12-2010

Amount: $580,090.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP180101421

Start Date: 2018

End Date: 07-2021

Amount: $347,072.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP220102124

Start Date: 07-2022

End Date: 06-2025

Amount: $564,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP220100896

Start Date: 03-2022

End Date: 03-2025

Amount: $350,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100181

Start Date: 03-2012

End Date: 12-2015

Amount: $650,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP110100327

Start Date: 2011

End Date: 12-2014

Amount: $300,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP160103414

Start Date: 2016

End Date: 12-2018

Amount: $359,700.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP150101097

Start Date: 2015

End Date: 12-2018

Amount: $354,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0884027

Start Date: 06-2009

End Date: 02-2013

Amount: $450,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE190100021

Start Date: 09-2019

End Date: 09-2022

Amount: $4,320,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP130102153

Start Date: 2013

End Date: 12-2016

Amount: $946,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE160100051

Start Date: 2016

End Date: 12-2018

Amount: $3,000,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0882357

Start Date: 2008

End Date: 01-2009

Amount: $500,000.00

Funder: Australian Research Council

ARC Centres Of Excellence - Grant ID: CE230100021

Start Date: 12-2023

End Date: 12-2030

Amount: $35,000,000.00

Funder: Australian Research Council