ORCID Profile
0000-0002-6324-442X
Current Organisation
Australian National University
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biochemistry and Cell Biology | Structural Biology (incl. Macromolecular Modelling) | Neurosciences Not Elsewhere Classified | Nanotechnology | Membrane and Separation Technologies | Quantum Chemistry | Plant Biochemistry And Physiology | Transport Properties and Non-Equilibrium Processes | Cell Physiology | Receptors and Membrane Biology | Biophysics | Biological Sciences Not Elsewhere Classified | Central Nervous System | Other Physical Sciences | Other Biological Sciences | Protein Targeting And Signal Transduction | Membrane Biology | Materials Engineering | Neurology and Neuromuscular Diseases | Neurosciences | Composite and Hybrid Materials |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Education and Training Theory and Methodology | Nervous System and Disorders | Infectious diseases | Nervous system and disorders | Higher education | Biological sciences | Inherited diseases (incl. gene therapy) | Physical sciences | Water Services and Utilities | International relations not elsewhere classified | Physical and Chemical Conditions of Water for Urban and Industrial Use | Field crops not elsewhere classified | Cardiovascular System and Diseases | Expanding Knowledge in the Physical Sciences | Diagnostics
Related Links
Publications
An improved open-channel structure of MscL determined from FRET confocal microscopy and simulation
Publisher: Rockefeller University Press
Date: 27-09-2010
Abstract: Mechanosensitive channels act as molecular transducers of mechanical force exerted on the membrane of living cells by opening in response to membrane bilayer deformations occurring in physiological processes such as touch, hearing, blood pressure regulation, and osmoregulation. Here, we determine the likely structure of the open state of the mechanosensitive channel of large conductance using a combination of patch cl , fluorescence resonance energy transfer (FRET) spectroscopy, data from previous electron paramagnetic resonance experiments, and molecular and Brownian dynamics simulations. We show that structural rearrangements of the protein can be measured in similar conditions as patch cl recordings while controlling the state of the pore in its natural lipid environment by modifying the lateral pressure distribution via the lipid bilayer. Transition to the open state is less dramatic than previously proposed, while the N terminus remains anchored at the surface of the membrane where it can either guide the tilt of or directly translate membrane tension to the conformation of the pore-lining helix. Combining FRET data obtained in physiological conditions with simulations is likely to be of great value for studying conformational changes in a range of multimeric membrane proteins.
Dielectric Self-Energy in Poisson-Boltzmann and Poisson-Nernst-Planck Models of Ion Channels
Publisher: Elsevier BV
Date: 06-2003
Do bifunctional labels solve the problem of dye diffusion in FRET analysis?
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4CP02110J
Abstract: We examine the potential application of bifunctional dyes in Förster resonance energy transfer (FRET) experiments due to their increasing popularity in electron paramagnetic resonance spectroscopy.
Dynamics of Fluorescent Dyes Attached to G-Quadruplex DNA and their Effect on FRET Experiments
Publisher: Wiley
Date: 14-07-2015
Abstract: FRET spectroscopy is a promising approach for investigating the dynamics of G-quadruplex DNA folds and improving the targeting of G-quadruplexes by potential anticancer compounds. To better interpret such experiments, classical and replica-exchange molecular dynamics simulations and fluorescence-lifetime measurements are used to understand the behavior of a range of Cy3-based dyes attached to the 3' end of G-quadruplex DNA. The simulations revealed that the dyes interact extensively with the G-quadruplex. Identification of preferred dye positions relative to the G-quadruplex in the simulations allows the impact of dye-DNA interactions on FRET results to be determined. All the dyes show significant deviations from the common approximation of being freely rotating and not interacting with the host, but one of the Cy3 dye analogues is slightly closer to this case.
Computational study of the transmembrane domain of the acetylcholine receptor
Publisher: Springer Science and Business Media LLC
Date: 23-05-2009
DOI: 10.1007/S00249-009-0476-3
Abstract: The nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel protein whose transmembrane domain (TM-domain) is believed to be responsible for channel gating via a hydrophobic effect. In this work, we perform molecular dynamics and Brownian dynamics simulations to investigate the effect of transmembrane potential on the conformation and water occupancy of TM-domain, and the resulting ion permeation events. The results show that the behavior of the hydrophobic gate is voltage-dependent. Large hyperpolarized membrane potential can change the conformation of TM-domain and water occupancy in this region, which may enable ion conduction. An electrostatic gating mechanism is also proposed from our simulations, which seems to play a role in addition to the well-known hydrophobic effect.
Molecular dynamics simulations of structure and dynamics of organic molecular crystals
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C0CP01409E
Abstract: A set of model compounds covering a range of polarity and flexibility have been simulated using GAFF, CHARMM22, OPLS and MM3 force fields to examine how well classical molecular dynamics simulations can reproduce structural and dynamic aspects of organic molecular crystals. Molecular structure, crystal structure and thermal motion, including molecular reorientations and internal rotations, found from the simulations have been compared between force fields and with experimental data. The MM3 force field does not perform well in condensed phase simulations, while GAFF, CHARMM and OPLS perform very similarly. Generally molecular and crystal structure are reproduced well, with a few exceptions. The atomic displacement parameters (ADPs) are mostly underestimated in the simulations with a relative error of up to 70%. Ex les of molecular reorientation and internal rotation, observed in the simulations, include in-plane reorientations of benzene, methyl rotations in alanine, decane, isopropylcyclohexane, pyramidal inversion of nitrogen in amino group and rotation of the whole group around the C-N bond. Frequencies of such dynamic processes were calculated, as well as thermodynamic properties for reorientations in benzene and alanine. We conclude that MD simulations can be used for qualitative analysis, while quantitative results should be taken with caution. It is important to compare the outcomes from simulations with as many experimental quantities as available before using them to study or quantify crystal properties not available from experiment.
Test of Poisson-Nernst-Planck Theory in Ion Channels
Publisher: Rockefeller University Press
Date: 27-09-1999
Testing the Applicability of Nernst-Planck Theory in Ion Channels: Comparisons with Brownian Dynamics Simulations
Publisher: Public Library of Science (PLoS)
Date: 23-06-2011
The role of MscL amphipathic N terminus indicates a blueprint for bilayer-mediated gating of mechanosensitive channels
Publisher: Springer Science and Business Media LLC
Date: 22-06-2016
DOI: 10.1038/NCOMMS11984
Abstract: The bacterial mechanosensitive channel MscL gates in response to membrane tension as a result of mechanical force transmitted directly to the channel from the lipid bilayer. MscL represents an excellent model system to study the basic biophysical principles of mechanosensory transduction. However, understanding of the essential structural components that transduce bilayer tension into channel gating remains incomplete. Here using multiple experimental and computational approaches, we demonstrate that the hipathic N-terminal helix of MscL acts as a crucial structural element during tension-induced gating, both stabilizing the closed state and coupling the channel to the membrane. We propose that this may also represent a common principle in the gating cycle of unrelated mechanosensitive ion channels, allowing the coupling of channel conformation to membrane dynamics.
Intrinsic Ion Selectivity of Narrow Hydrophobic Pores
Publisher: American Chemical Society (ACS)
Date: 06-05-2009
DOI: 10.1021/JP810102U
Abstract: We show that narrow hydrophobic pores have an intrinsic ion selectivity by using single-walled carbon nanotube membranes as a model. We examined pores of radius 3.4-6.1 A, and conducted molecular dynamics simulations to show that Na+, K+, and Cl- face different free energy barriers when entering hydrophobic pores. Most of the differences result from the different dehydration energies of the ions however, changes in the solvation shell structure in the confined nanotube interior and van der Waals interactions in the small tubes can both play a role. Molecular dynamics simulations conducted under hydrostatic pressure show that carbon nanotube membranes can act as ion sieves, with the pore radius and pressure determining which ions will permeate through the membrane. This work suggests that the intrinsic ion selectivity of biological pores of differing radii might also play a role in determining their selectivity, in addition to the more common explanations based on electrostatic effects. In addition, "hydrophobic gating" can arise in continuous water-filled pores.
Mapping the importance of four factors in creating monovalent ion selectivity in biological molecules
Publisher: Elsevier BV
Date: 2011
Influence of protein flexibility on the electrostatic energy landscape in gramicidin A
Publisher: Springer Science and Business Media LLC
Date: 05-11-2004
DOI: 10.1007/S00249-004-0442-Z
Abstract: We describe an electrostatic model of the gramicidin A channel that allows protein atoms to move in response to the presence of a permeating ion. To do this, molecular dynamics simulations are carried out with a permeating ion at various positions within the channel. Then an ensemble of atomic coordinates taken from the simulations are used to construct energy profiles using macroscopic electrostatic calculations. The energy profiles constructed are compared to experimentally-determined conductance data by inserting them into Brownian dynamics simulations. We find that the energy landscape seen by a permeating ion changes significantly when we allow the protein atoms to move rather than using a rigid protein structure. However, the model developed cannot satisfactorily reproduce all of the experimental data. Thus, even when protein atoms are allowed to move, the dielectric model used in our electrostatic calculations breaks down when modeling the gramicidin channel.
A Flexible Approach to the Calculation of Resonance Energy Transfer Efficiency between Multiple Donors and Acceptors in Complex Geometries
Publisher: Elsevier BV
Date: 12-2005
Fluorescent Triphenyl Substituted Maleimide Derivatives: Synthesis, Spectroscopy and Quantum Chemical Calculations
Publisher: Springer Science and Business Media LLC
Date: 15-04-2010
DOI: 10.1007/S10895-010-0660-Y
Abstract: In this paper we describe a semi-empirical quantum method for predicting the wavelength of maximum fluorescence excitation and emission for several known and new maleimide derivatives. All new maleimides, containing a N-Benzyl attachment, were successfully synthesised via a tandem Suzuki reaction with aryl boronic acids containing either an electron donating, electron withdrawing functional groups. Absorption and emission spectra calculated using the semi-empirical AM1 method with excited state ZINDO calculations proved more reliable than either Hartree-Fock Configuration interaction or time dependent density functional methods. Calculated absorption and emission wavelengths were compared with 26 experimental spectra from known or newly synthesised maleimides and found to have provide reasonable predictions, with an average deviation of less the 6% for absorption maxima and less than 4% for emission peaks. The described method provides a strong benchmark for the accuracy that can be expected from theoretical predictions of fluorescence spectra.
Quantifying barriers to monovalent anion transport in narrow non-polar pores
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2CP41641G
Abstract: The transport of anionic drinking water contaminants (fluoride, chloride, nitrate and nitrite) through narrow pores ranging in effective radius from 2.5 to 6.5 Å was systematically evaluated using molecular dynamics simulations to elucidate the magnitude and origin of energetic barriers encountered in nanofiltration. Free energy profiles for ion transport through the pores show that energy barriers depend on pore size and ion properties and that there are three key regimes that affect transport. The first is where the ion can fit in the pore with its full inner hydration shell, the second is where the pore size is between the bare ion and hydrated radius, and the third is where the ion size approaches that of the pore. Energy barriers in the first regime are relatively small and due to rearrangement of the inner hydration shell and/or displacement of further hydration shells. Energy barriers in the second regime are due to partial dehydration and are larger than barriers seen in the first regime. In the third regime, the pore becomes too small for bare ions to fit regardless of hydration and thus energy barriers are very high. In the second regime where partial dehydration controls transport, the trend in the slopes of the change in energy barrier with pore size corresponds to the hydration strength of the anions.
Computational studies of Piezo1 yield insights into key lipid–protein interactions, channel activation, and agonist binding
Publisher: Springer Science and Business Media LLC
Date: 13-10-2022
Physical basis of specificity and delayed binding of a subtype selective sodium channel inhibitor
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41598-018-19850-9
Abstract: Nerve and muscle signalling is controlled by voltage-gated sodium (Nav) channels which are the targets of local anesthetics, anti-epileptics and anti-arrythmics. Current medications do not selectively target specific types of Nav found in the body, but compounds that do so have the potential to be breakthrough treatments for chronic pain, epilepsy and other neuronal disorders. We use long computer simulations totaling more than 26 μ s to show how a promising lead compound can target one Nav implicated in pain perception and specific channels found in bacteria, and accurately predict the affinity of the compound to different channel types. Most importantly, we provide two explanations for the slow kinetics of this class of compound that limits their therapeutic utility. Firstly, the negative charge on the compound is essential for high affinity binding but is also responsible for energetic barriers that slow binding. Secondly, the compound has to undergo a conformational reorientation during the binding process. This knowledge aids the design of compounds affecting specific eukaryotic and bacterial channels and suggests routes for future drug development.
An Entropic Mechanism of Generating Selective Ion Binding in Macromolecules
Publisher: Public Library of Science (PLoS)
Date: 28-02-2013
Mechanisms of valence selectivity in biological ion channels
Publisher: Springer Science and Business Media LLC
Date: 02-01-2006
DOI: 10.1007/S00018-005-5405-8
Abstract: Transmembrane ion channels play a crucial role in the existence of all living organisms. They partition the exterior from the interior of the cell, maintain the proper ionic gradient across the cell membrane and facilitate signaling between cells. To perform these functions, ion channels must be highly selective, allowing some types of ions to pass while blocking the passage of others. Here we review a number of studies that have helped to elucidate the mechanisms by which ion channels discriminate between ions of differing charge, focusing on four channel families as ex les: gramicidin, ClC chloride, voltage-gated calcium and potassium channels. The recent availability of high-resolution structural data has meant that the specific inter-atomic interactions responsible for valence selectivity can be pinpointed. Not surprisingly, electrostatic considerations have been shown to play an important role in ion specificity, although many details of the origins of this discrimination remain to be determined.
Accounting for dye diffusion and orientation when relating FRET measurements to distances: three simple computational methods
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4CP01222D
Abstract: A detailed analysis of three simple methods that account for dye diffusion and orientation when relating FRET measurements to distances.
Characterizing the lipid fingerprint of the mechanosensitive channel Piezo2
Publisher: Rockefeller University Press
Date: 21-07-2022
Abstract: Piezo2 is a mechanosensitive ion channel that plays critical roles in sensing touch and pain, proprioception, and regulation of heart rate. Global knockout of Piezo2 leads to perinatal lethality in mice, and Piezo2 gain-of-function mutations are associated with distal arthrogryposis, a disease characterized by congenital joint contractures. Emerging evidence suggests that Piezo channels (Piezo1 and Piezo2) can be regulated by their local membrane environment and particularly by cholesterol and phosphoinositides. To characterize the local Piezo2 lipid environment and investigate key lipid–protein interactions, we carried out coarse-grained molecular dynamics simulations of Piezo2 embedded in a complex mammalian membrane containing & distinct lipid species. We show that Piezo2 alters its local membrane composition such that it becomes enriched with specific lipids, such as phosphoinositides, and forms specific, long-term interactions with a variety of lipids at functionally relevant sites.
New insights from modelling studies and molecular dynamics simulations of the DIS5‐S6 extracellular linker of the skeletal muscle sodium channel NaV1.4
Publisher: Wiley
Date: 31-05-2023
DOI: 10.1002/BIP.23540
Abstract: In the CryoEM‐structure of the hSkMNaV1.4 ion channel (PDB:6AGF), the 59‐residue DI S5‐S6 linker peptide was omitted due to absence of electron density. This peptide is intriguing – comprised of unique sequence and found only in mammalian skeletal muscle sodium ion channels. To probe potential physiological and evolutionary significance, we constructed an homology model of the complete hSkMNaV1.4 channel. Rather than a flexible random coil potentiating drift across the channel, the linker folds into a compact configuration through self‐assembling secondary structural elements. Analogous sequences from 48 mammalian organisms show hypervariability with between 40% and 100% sequence similarity. To investigate structural implications, sequences from 14 representative organisms were additionally modelled. All showed highly conserved N‐and C‐terminal residues closely superimposed, suggesting a critical functional role. An optimally located asparagine residue within the conserved region was investigated for N‐linked glycosylation and MD simulations carried out. Results suggest a complex glycan added at this site in the linker may form electrostatic interactions with the DIV voltage sensing domain and be mechanistically involved in channel gating. The relationship of unique sequence, compact configuration, potential glycosylation and MD simulations are discussed relative to SkMNaV1.4 structure and function.
Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels
Publisher: Proceedings of the National Academy of Sciences
Date: 21-02-2018
Abstract: Voltage-gated sodium channels are integral in electrical signaling within the human body and are key targets for anesthetics and antiepileptic compounds used in surgeries and the treatment of neurological disorders. We have used molecular simulations to determine where a number of these compounds bind inside the pore of a voltage-gated sodium channel to aid the design of new compounds for treating chronic pain, heart conditions, and epilepsy. We uncover two distinct binding sites inside the pore harnessed by neutral and charged drugs, respectively. This explains why so many anesthetic compounds have both neutral and charged forms: The neutral form more easily enters the pore, but the charged form binds more tightly to effectively block the pore and prevent electrical signaling.
Binding of azobenzene and p-diaminoazobenzene to the human voltage-gated sodium channel Nav1.4
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0CP06140A
Abstract: The binding of two photoswitches to the human voltage-gated sodium channel Na V 1.4 was computationally investigated, and the main interactions involved in the process were unveiled and characterized.
Continuum Electrostatics Fails to Describe Ion Permeation in the Gramicidin Channel
Publisher: Elsevier BV
Date: 09-2002
Na+/Ca2+selectivity in the bacterial voltage-gated sodium channel NavAb
Publisher: PeerJ
Date: 12-02-2013
DOI: 10.7717/PEERJ.16
Quantitative Förster resonance energy transfer efficiency measurements using simultaneous spectral unmixing of excitation and emission spectra
Publisher: SPIE-Intl Soc Optical Eng
Date: 19-02-2013
Molecular dynamics simulation of the partitioning of benzocaine and phenytoin into a lipid bilayer
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.BPC.2013.12.003
Abstract: Molecular dynamics simulations were used to examine the partitioning behaviour of the local anaesthetic benzocaine and the anti-epileptic phenytoin into lipid bilayers, a factor that is critical to their mode of action. Free energy methods are used to quantify the thermodynamics of drug movement between water and octanol as well as for permeation across a POPC membrane. Both drugs are shown to favourably partition into the lipid bilayer from water and are likely to accumulate just inside the lipid headgroups where they may alter bilayer properties or interact with target proteins. Phenytoin experiences a large barrier to cross the centre of the bilayer due to less favourable energetic interactions in this less dense region of the bilayer. Remarkably, in our simulations both drugs are able to pull water into the bilayer, creating water chains that extend back to bulk, and which may modify the local bilayer properties. We find that the choice of atomic partial charges can have a significant impact on the quantitative results, meaning that careful validation of parameters for new drugs, such as performed here, should be performed prior to their use in biomolecular simulations.
Determination of the orientational distribution and orientation factor for transfer between membrane-bound fluorophores using a confocal microscope
Publisher: Elsevier BV
Date: 08-2006
Author Response: A binding site for phosphoinositide modulation of voltage-gated sodium channels described by multiscale simulations
Publisher: eLife Sciences Publications, Ltd
Date: 05-10-2023
Bacterial mechanosensitive channels: Experiment and theory
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.BBAMEM.2007.06.022
Abstract: Since their discovery in Escherichia coli some 20 years ago, studies of bacterial mechanosensitive (MS) ion channels have been at the forefront of the MS channel research field. Two major events greatly advanced the research on bacterial MS channels: (i) cloning of MscL and MscS, the MS channels of Large and Small conductance, and (ii) solving their 3D crystal structure. These events enabled further experimental studies employing EPR and FRET spectroscopy in addition to patch cl and molecular biological techniques that have successfully been used in characterization of the structure and function of bacterial MS channels. In parallel with the experimental studies computational modelling has been applied to elucidate the molecular dynamics of MscL and MscS, which has significantly contributed to our understanding of basic physical principles of the mechanosensory transduction in living organisms.
Conformational changes involved in MscL channel gating measured using FRET spectroscopy
Publisher: Elsevier BV
Date: 12-2005
Brownian dynamics investigation into the conductance state of the MscS channel crystal structure
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.BBAMEM.2006.04.014
Abstract: We suggest that the crystal structure of the mechanosensitive channel of small conductance is in a minimally conductive state rather than being fully activated. Performing Brownian dynamics simulations on the crystal structure show that no ions pass through it. When simulations are conducted on just the transmembrane domain (excluding the cytoplasmic residues 128 to 280) ions are seen to pass through the channel, but the conductance of approximately 30 pS is well below experimentally measured values. The mutation L109S that replaces a pore lining hydrophobic residue with a polar one is found to have little effect on the conductance of the channel. Widening the hydrophobic region of the pore by 2.5 Angstrom however, increases the channel conductance to over 200 pS suggesting that only a minimal conformational change is required to gate the pore.
The Fast Gating Mechanism in ClC-0 Channels
Publisher: Elsevier BV
Date: 07-2005
Simulation of Structure, Orientation, and Energy Transfer between AlexFluor Molecules Attached to MscL
Publisher: Elsevier BV
Date: 09-2008
Response to Comment on “Experimental Energy Barriers to Anions Transporting through Nanofiltration Membranes”
Publisher: American Chemical Society (ACS)
Date: 17-07-2013
DOI: 10.1021/ES402784J
Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins
Publisher: Informa UK Limited
Date: 18-03-2016
A microfluidic platform to synthesise a G-quadruplex binding ligand
Publisher: Royal Society of Chemistry (RSC)
Date: 2009
DOI: 10.1039/B902986A
Abstract: An aromatic triarylpyridine chromophore promotes pi-stacking interactions with the terminal G-tetrad in quadruplex DNA, stabilizing the structure and presenting a pathway towards cancer treatment by inhibition of telomerase. An interesting parent compound in this class is the dimethylamino functionalised 4'-aryl-2,6-bis(4-aminophenyl)pyridine. However, access to this compound using traditional batch synthetic methodology is limited, due to thermodynamic and kinetic constraints. A novel approach to the synthesis of this compound has been developed, involving dynamic thin films, overcoming a series of competing reactions, effectively controlling chemical reactivity and selectivity.
An Energy-Efficient Gating Mechanism in the Acetylcholine Receptor Channel Suggested by Molecular and Brownian Dynamics
Publisher: Elsevier BV
Date: 02-2006
Mechanism of the dehydrogenase reaction of DmpFG and analysis ofinter-subunit channeling efficiency and thermodynamic parametersin the overall reaction
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.BIOCEL.2013.05.028
Abstract: The bifunctional, microbial enzyme DmpFG is comprised of two subunits: the aldolase, DmpG, and the dehydrogenase, DmpF. DmpFG is of interest due to its ability to channel substrates between the two spatially distinct active sites. While the aldolase is well studied, significantly less is known about the dehydrogenase. Steady-state kinetic measurements of the reverse reaction of DmpF confirmed that the dehydrogenase uses a ping-pong mechanism, with substrate inhibition by acetyl CoA indicating that NAD(+)/NADH and CoA/acetyl CoA bind to the same site in DmpF. The Km of DmpF for exogenous acetaldehyde as a substrate was 23.7 mM, demonstrating the necessity for the channel to deliver acetaldehyde directly from the aldolase to the dehydrogenase active site. A channeling assay on the bifunctional enzyme gave an efficiency of 93% indicating that less than 10% of the toxic acetaldehyde leaks out of the channel into the bulk media, prior to reaching the dehydrogenase active site. The thermodynamic activation parameters of the reactions catalyzed by the aldolase, the dehydrogenase and the DmpFG complex were determined. The Gibb's free energy of activation for the dehydrogenase reaction was lower than that obtained for the full DmpFG reaction, in agreement with the high kcat obtained for the dehydrogenase reaction in isolation. Furthermore, although both the DmpF and DmpG reactions occur with small, favorable entropies of activation, the full DmpFG reaction occurs with a negative entropy of activation. This supports the concept of allosteric structural communication between the two enzymes to coordinate their activities.
Mechanisms of selective ion transport and salt rejection in carbon nanostructures
Publisher: Springer Science and Business Media LLC
Date: 04-2017
DOI: 10.1557/MRS.2017.56
A model of sodium channels
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.BBAMEM.2004.11.011
Abstract: We have explored the permeation and blockage of ions in sodium channels, relating the channel structure to function using electrostatic profiles and Brownian dynamics simulations. The model used resembles the KcsA potassium channel with an added external vestibule and a shorter selectivity filter. The electrostatic energy landscape seen by permeating ions is determined by solving Poisson's equation. The two charged amino acid rings of Glu-Glu-Asp-Asp (EEDD) and Asp-Glu-Lys-Ala (DEKA) around the selectivity filter region are seen to play a crucial role in making the channel sodium selective, and strongly binding calcium ions such that they block the channel. Our model closely reproduces a range of experimental data including the current-voltage curves, current-concentration curves and blockage of monovalent ions by alent ions.
The confined space inside carbon nanotubes can dictate the stereo- and regioselectivity of Diels-Alder reactions
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3CP54295E
Abstract: Chemical reactions inside carbon nanotubes can yield unusual outcomes. Molecular dynamics simulations show that within the confined space of carbon nanotubes, the 1,4-exo adduct of a Diels-Alder cycloaddition may be produced instead of the 9,10-adduct, which is favoured in bulk. The likely product is highly dependent on the nanotube radius and reactant size.
Piezo1 Forms Specific, Functionally Important Interactions with Phosphoinositides and Cholesterol
Publisher: Elsevier BV
Date: 10-2020
Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel
Publisher: Public Library of Science (PLoS)
Date: 03-07-2014
Modifying Water Flow, Ion Selectivity, and Salt Rejection in Carbon Nanotubes via Surface Adsorption
Publisher: American Chemical Society (ACS)
Date: 21-01-2020
Temperature dependence of rotational disorder in a non-standard amino acid from X-ray crystallography and molecular dynamics simulation
Publisher: Royal Society of Chemistry (RSC)
Date: 2009
DOI: 10.1039/B819157C
Abstract: The X-ray single-crystal structure of methyl 2-aminoisobutyrate hydrochloride (Me-AIB), a non-standard amino acid, is reported at 10, 30, 50, 70 and 100 K. Fourier maps indicate the presence of rotational disorder of the hydrogen atoms of the ester methyl group. To study this effect in detail, high resolution data were collected with synchrotron radiation. The non-spherical molecular electron density was predicted with invariom scattering factors and subtracted from the density obtained from a full multipole refinement. This allows disorder to be distinguished from the molecular electron density at each temperature. The disorder is reduced between 100 K and 30 K, but still detectable even at 10 K. Hence, difference densities can be applied for the purpose of electronic structure validation and have the advantage of an absence of noise over Fourier methods. Ultra-low temperature experiments are foreseen to be useful in reducing such kinds of disorder in ultra-high resolution protein crystallography. Molecular dynamics simulations of Me-AIB at temperatures between 10 and 100 K confirm the temperature dependence of the rotational motion of the methyl group seen experimentally. Modeling disorder in X-ray structure analysis will be an interesting future application of molecular dynamics simulations.
MyoD-family inhibitor proteins act as auxiliary subunits of Piezo channels
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-08-2023
Abstract: Piezo channels are critical cellular sensors of mechanical forces. Despite their large size, ubiquitous expression, and irreplaceable roles in an ever-growing list of physiological processes, few Piezo channel–binding proteins have emerged. In this work, we found that MyoD (myoblast determination)–family inhibitor proteins (MDFIC and MDFI) are PIEZO1/2 interacting partners. These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryogenic electron microscopy, we mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These Piezo-interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous Piezo channels observed in many cell types, and elucidate mechanisms potentially involved in human lymphatic vascular disease.
Redox control of calcium channels: From mechanisms to therapeutic opportunities
Publisher: Mary Ann Liebert Inc
Date: 04-2007
Abstract: Calcium plays an integral role in cellular function. It is a well-recognized second messenger necessary for signaling cellular responses, but in excessive amounts can be deleterious to function, causing cell death. The main route by which calcium enters the cytoplasm is either from the extracellular compartment or internal addistores via calcium channels. There is good evidence that calcium channels can respond to pharmacological compounds that reduce or oxidize thiol groups on the channel protein. In addition, reactive oxygen species such as hydrogen peroxide and superoxide that can mediate oxidative pathology also mediate changes in channel function via alterations of thiol groups. This review looks at the structure and function of calcium channels, the evidence that changes in cellular redox state mediate changes in channel function, and the role of redox modification of channels in disease processes. Understanding how redox modification of the channel protein alters channel structure and function is providing leads for the design of therapeutic interventions that target oxidative stress responses.
Mechanisms of Permeation and Selectivity in Calcium Channels
Publisher: Elsevier BV
Date: 2001
A model of calcium channels
Publisher: Elsevier BV
Date: 12-2000
DOI: 10.1016/S0005-2736(00)00330-8
Abstract: We propose a model of calcium channels that can explain most of their observed properties, including the anomalous mole fraction effect and mutation of the glutamate residues. The structure grossly resembles that of the KcsA potassium channel except for the presence of an extracellular vestibule and a shorter selectivity filter containing four glutamate residues. Using this model in electrostatic calculations and Brownian dynamics simulations, we study mechanisms of ion permeation and selectivity in the channel. Potential energy profiles calculated for multiple ions in the channel provide explanations of ion permeation, the block of Na(+) currents by Ca(2+) ions, and many other observed properties. Brownian dynamics simulations provide quantitative predictions for the channel currents which reproduce available experimental data.
Simulations of Guest Transport in Clathrates of Dianin's Compound and Hydroquinone
Publisher: Wiley
Date: 07-01-2013
Abstract: Clathrates have been proposed for use in a variety of applications including gas storage, mixture separation and catalysis due to the potential for controlled guest diffusion through their porous lattices. Here molecular dynamics simulations are employed to study guest transport in clathrates of hydroquinone (HQ) and Dianin's compound (DC). Systems investigated were HQ with methanol and acetonitrile, and DC with methanol and ethanol. Simulations were set up with one guest in the pore, two guests in the pore and one vacancy in the pore and a filled pore, and free-energy barriers for movement between cavities of the pore were estimated for all cases. Comparison between these simulations indicates that guest transport most likely proceeds by molecules moving from full to empty cavities consecutively, one by one, rather than in a concerted manner. Thus, the presence of empty cavities is very important for guest transport, which becomes more energetically demanding in fully loaded systems. Flexibility of the host can assist guest transport. In the studied DC clathrates transport occurs via an intermediate conformation in which the hydroxyl group of the alcohol guest molecule participates in the hydrogen-bonded ring of the host. We also address the issue of the number of methanol guest molecules that DC accommodates, for which conflicting information exists. We found that this is likely to be temperature dependent and suggest that under some conditions the system is most likely non-stoichiometric.
Characterizing fenestration size in sodium channel subtypes and their accessibility to inhibitors
Publisher: Elsevier BV
Date: 2022
A roadmap to generate renewable protein binders to the human proteome
Publisher: Springer Science and Business Media LLC
Date: 15-05-2011
DOI: 10.1038/NMETH.1607
Abstract: Despite the wealth of commercially available antibodies to human proteins, research is often hindered by their inconsistent validation, their poor performance and the inadequate coverage of the proteome. These issues could be addressed by systematic, genome-wide efforts to generate and validate renewable protein binders. We report a multicenter study to assess the potential of hybridoma and phage-display technologies in a coordinated large-scale antibody generation and validation effort. We produced over 1,000 antibodies targeting 20 SH2 domain proteins and evaluated them for potency and specificity by enzyme-linked immunosorbent assay (ELISA), protein microarray and surface plasmon resonance (SPR). We also tested selected antibodies in immunoprecipitation, immunoblotting and immunofluorescence assays. Our results show that high-affinity, high-specificity renewable antibodies generated by different technologies can be produced quickly and efficiently. We believe that this work serves as a foundation and template for future larger-scale studies to create renewable protein binders.
Role of acetylcholine receptor domains in ion selectivity
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.BBAMEM.2009.04.015
Abstract: The nicotinic acetylcholine receptor (nAChR) is a ligand gated ion channel protein, composed of three domains: a transmembrane domain (TM-domain), extracellular domain (EC-domain), and intracellular domain (IC-domain). Due to its biological importance, much experimental and theoretical research has been carried out to explore its mechanisms of gating and selectivity, but there are still many unresolved issues, especially on the ion selectivity. Moreover, most of the previous theoretical work has concentrated on the TM-domain or EC-domain of nAChR, which may be insufficient to understand the entire structure-function relation. In this work, we perform molecular dynamics, Brownian dynamics simulations and continuum electrostatic calculations to investigate the role of different nAChR domains in ion conduction and selectivity. The results show that although both the EC and IC domains contain strong negative charges that create large cation concentrations at either end of the pore, this alone is not sufficient to create the observed cation selectivity and may play a greater role in determining the channel conductance. The presence of cations in the wide regions of the pore can screen out the protein charge allowing anions to enter, meaning that local regions of the TM-domain are most likely responsible for discriminating between ions. These new results complement our understanding about the ion conduction and selectivity mechanism of nAChR.
Enhancing the efficacy of cation-independent mannose 6-phosphate receptor inhibitors by intracellular delivery
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5CC06826F
Abstract: Intracellular delivery of M6P/IGFII receptor inhibitors exhibits better efficacy than extracellular inhibitors to regulate TGFβ 1 mediated upregulation of profibrotic marker, collagen I.
Theoretical conformation of the closed and open states of the acetylcholine receptor channel
Publisher: Elsevier BV
Date: 05-2004
Designing a biomimetic graphene nanopore with valence selectivity between cations
Publisher: Elsevier BV
Date: 08-2023
Binding and Channeling of Alternative Substrates in the Enzyme DmpFG: a Molecular Dynamics Study
Publisher: Elsevier BV
Date: 04-2014
Experimental Energy Barriers to Anions Transporting through Nanofiltration Membranes
Publisher: American Chemical Society (ACS)
Date: 08-02-2013
DOI: 10.1021/ES303925R
Abstract: Environmentally relevant contaminants fluoride, chloride, nitrate, and nitrite face Arrhenius energy barriers during transport through nanofiltration (NF) membranes. The energy barriers were quantified using crossflow filtration experiments and were in the range of 7-17 kcal·mol(-1), according to ion type and membrane type (Filmtec NF90 and NF270). Fluoride faced a comparatively high energy barrier for both membranes. This can be explained by the strong hydration energy of fluoride rather than other ion properties such as bare ion radius, fully hydrated radius, Stokes radius, diffusion coefficient, or ion charge. The energy barrier for fluoride decreased with pressure, indicating an impact of directional force on energy barriers. The influence of temperature-induced pore radius variability and viscosity on energy barriers was considered. The novel link between energy barriers and ion properties emphasizes the importance of ion hydration and/or partial dehydration mechanisms in determining transport in NF.
Mechanism of Concerted Hydrogen Bond Reorientation in Clathrates of Dianin's Compound and Hydroquinone
Publisher: American Chemical Society (ACS)
Date: 28-10-2011
DOI: 10.1021/JA206962F
Abstract: Molecular dynamics provides a means to examine the mechanism of reorientation of hydrogen bond networks that are present in a range of biological and crystalline materials. Simulations of hydroxyl reorientation in the six-membered hydrogen bonded rings in crystalline clathrates of Dianin's compound (DC) and hydroquinone (HQ) reveal that in the clathrate of Dianin's compound with ethanol (DC:ethanol), hydroxyl groups perform single independent flips, and occasionally all six hydroxyls in a ring reorient following a sequential mechanism with participation of the guest ethanol molecule. The free energy estimated for this process agrees well with experimental results. The simulations suggest that hydroxyl reorientation occurs in the empty DC lattice as well, but at a higher energy cost, from which we conclude that it is the participation of ethanol that lowers the barrier of reorientation. Single independent flips of hydroxyl groups are observed to be more frequent in the hydroquinone clathrate with methanol (HQ:methanol) than in DC:ethanol, but reorientation of all six hydroxyls does not occur. This is attributed to the larger difference in energy between the original and reoriented positions of hydroxyl hydrogen atoms in HQ:methanol compared to DC:ethanol.
ExiFRET: flexible tool for understanding FRET in complex geometries
Publisher: SPIE-Intl Soc Optical Eng
Date: 2012
Piezo1 Induces Local Curvature in a Mammalian Membrane and Forms Specific Protein-Lipid Interactions
Publisher: Cold Spring Harbor Laboratory
Date: 30-09-2019
DOI: 10.1101/787531
Abstract: Touch, hearing, and blood pressure control require mechanically-gated ion channels that convert mechanical stimuli into electrical currents. Piezo1 and Piezo2 were recently identified as essential eukaryotic mechanically-gated ion channels, yet how they respond to physical forces remains poorly understood. Here we use a multi-disciplinary approach to interrogate the interaction of Piezo1 with its lipid environment. We show that in idual Piezo1 channels induce significant local curvature in the membrane that is magnified in a cooperative manner to generate larger curved ‘Piezo1 pits.’ Curvature decreases under lateral membrane tension, consistent with a hypothesis that force detection can involve sensing changes to local curvature. The protein alters its local membrane composition, enriching specific lipids and forming essential binding sites for phosphoinositides and cholesterol that are functionally relevant and often related to Piezo1-mediated pathologies. Finally, we show that Piezo1 alters the expression of lipid-regulating proteins and modifies the cellular lipidome. In short, we find that lipids influence Piezo1 activity and Piezo1 influences the local morphology and composition of the bilayer as well as the cellular lipidome.
Identification of novel inhibitors of the amino acid transporter B0AT1 (SLC6A19), a potential target to induce protein restriction and to treat type 2 diabetes
Publisher: Wiley
Date: 14-02-2017
DOI: 10.1111/BPH.13711
A binding site for phosphoinositide modulation of voltage-gated sodium channels described by multiscale simulations
Publisher: eLife Sciences Publications, Ltd
Date: 05-10-2023
Bioinspired graphene nanopores with voltage-tunable ion selectivity for Na+ and K+
Publisher: American Chemical Society (ACS)
Date: 25-10-2013
DOI: 10.1021/NN4043628
Abstract: Biological protein channels have many remarkable properties such as gating, high permeability, and selectivity, which have motivated researchers to mimic their functions for practical applications. Herein, using molecular dynamics simulations, we design bioinspired nanopores in graphene sheets that can discriminate between Na(+) and K(+), two ions with very similar properties. The simulation results show that, under transmembrane voltage bias, a nanopore containing four carbonyl groups to mimic the selectivity filter of the KcsA K(+) channel preferentially conducts K(+) over Na(+). A nanopore functionalized by four negatively charged carboxylate groups to mimic the selectivity filter of the NavAb Na(+) channel selectively binds Na(+) but transports K(+) over Na(+). Surprisingly, the ion selectivity of the smaller diameter pore containing three carboxylate groups can be tuned by changing the magnitude of the applied voltage bias. Under lower voltage bias, it transports ions in a single-file manner and exhibits Na(+) selectivity, dictated by the knock-on ion conduction and selective blockage by Na(+). Under higher voltage bias, the nanopore is K(+)-selective, as the blockage by Na(+) is destabilized and the stronger affinity for carboxylate groups slows the passage of Na(+) compared with K(+). The computational design of biomimetic ion-selective nanopores helps to understand the mechanisms of selectivity in biological ion channels and may also lead to a wide range of potential applications such as sensitive ion sensors, nanofiltration membranes for Na(+)/K(+) separation, and voltage-tunable nanofluidic devices.
A binding site for phosphoinositide modulation of voltage-gated sodium channels described by multiscale simulations
Publisher: eLife Sciences Publications, Ltd
Date: 05-10-2023
DOI: 10.7554/ELIFE.91218
A mechanical nanogate based on a carbon nanotube for reversible control of ion conduction
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3NR06238D
Abstract: Ion conduction in nanofluidic devices can be reversibly controlled by regulating the ion hydration state with an AFM-tip deformable nanogate.
A computational assessment of the permeability and salt rejection of carbon nanotube membranes and their application to water desalination
Publisher: The Royal Society
Date: 13-02-2016
Abstract: Membranes made from nanomaterials such as nanotubes and graphene have been suggested to have a range of applications in water filtration and desalination, but determining their suitability for these purposes requires an accurate assessment of the properties of these novel materials. In this study, we use molecular dynamics simulations to determine the permeability and salt rejection capabilities for membranes incorporating carbon nanotubes (CNTs) at a range of pore sizes, pressures and concentrations. We include the influence of osmotic gradients and concentration build up and simulate at realistic pressures to improve the reliability of estimated membrane transport properties. We find that salt rejection is highly dependent on the applied hydrostatic pressure, meaning high rejection can be achieved with wider tubes than previously thought while membrane permeability depends on salt concentration. The ideal size of the CNTs for desalination applications yielding high permeability and high salt rejection is found to be around 1.1 nm diameter. While there are limited energy gains to be achieved in using ultra-permeable CNT membranes in desalination by reverse osmosis, such membranes may allow for smaller plants to be built as is required when size or weight must be minimized. There are diminishing returns in further increasing membrane permeability, so efforts should focus on the fabrication of membranes containing narrow or functionalized CNTs that yield the desired rejection or selection properties rather than trying to optimize pore densities.
Reservoir Boundaries in Brownian Dynamics Simulations of Ion Channels
Publisher: Elsevier BV
Date: 04-2002
Lipid redistribution in the highly curved footprint of Piezo1
Publisher: Elsevier BV
Date: 06-2023
DOI: 10.1016/J.BPJ.2022.07.022
Abstract: We investigate the effects on the distribution of lipids in the plasma membrane that are caused by the insertion of a protein, Piezo1, that significantly distorts the membrane toward the cytosol. From coarse-grained molecular dynamics simulations, we find that the major effects occur in the outer, extracellular, leaflet. The mol fraction of cholesterol increases significantly in the curved region of the membrane close to Piezo1, while those of phosphatidylcholine and of sphingomyelin decrease. In the inner leaflet, mol fractions of cholesterol and of phosphatidylethanolamine decrease slightly as the protein is approached, while that of phosphatidylserine increases slightly. The mol fraction of phosphatidylcholine decreases markedly as the protein is approached. Most of these results are understood in the context of a theoretical model that utilizes two elements: 1) a coupling between the leaflets' actual curvatures and their compositionally dependent spontaneous curvatures and 2) the dependence of the spontaneous curvatures not only on the mol fractions of the phospholipids, but also on the effect that cholesterol has on the spontaneous curvatures of the phospholipids.
The Predominant Role of Coordination Number in Potassium Channel Selectivity
Publisher: Elsevier BV
Date: 10-2007
Understanding ion channel selectivity and gating and their role in cellular signalling
Publisher: Royal Society of Chemistry (RSC)
Date: 2006
DOI: 10.1039/B610062G
Abstract: Ion channels play an essential role in the communication between and within cells. Here some of the different ion channel proteins and the roles they perform are introduced, before a discussion of the mechanisms by which they discriminate between different ion types and open and close to allow the passage of ions at the appropriate times.
Tests of Continuum Theories as Models of Ion Channels. II. Poisson–Nernst–Planck Theory versus Brownian Dynamics
Publisher: Elsevier BV
Date: 05-2000
Investigating the size and dynamics of voltage-gated sodium channel fenestrations
Publisher: Informa UK Limited
Date: 14-03-2014
DOI: 10.4161/CHAN.28136
Conduction Mechanisms of Chloride Ions in ClC-Type Channels
Publisher: Elsevier BV
Date: 02-2004
Anomalous decline of water transport in covalently modified carbon nanotube membranes
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1CC11134E
Abstract: Carbon nanotube membranes have been shown to rapidly transport liquids but progressive hydrophilic modification--contrary to expectations--induces a drastic reduction of water flow. Enhanced electrostatic interaction and the disruption of the mechanically smooth graphitic walls is the determinant of this behavior. These results have critical implications in the design of nanofluidic devices.
Mechanistic basis for multidrug resistance and collateral drug sensitivity conferred to the malaria parasite by polymorphisms in PfMDR1 and PfCRT
Publisher: Public Library of Science (PLoS)
Date: 04-05-2022
DOI: 10.1371/JOURNAL.PBIO.3001616
Abstract: Polymorphisms in the Plasmodium falciparum multidrug resistance protein 1 ( pfmdr1 ) gene and the Plasmodium falciparum chloroquine resistance transporter ( pfcrt ) gene alter the malaria parasite’s susceptibility to most of the current antimalarial drugs. However, the precise mechanisms by which PfMDR1 contributes to multidrug resistance have not yet been fully elucidated, nor is it understood why polymorphisms in pfmdr1 and pfcrt that cause chloroquine resistance simultaneously increase the parasite’s susceptibility to lumefantrine and mefloquine—a phenomenon known as collateral drug sensitivity. Here, we present a robust expression system for PfMDR1 in Xenopus oocytes that enables direct and high-resolution biochemical characterizations of the protein. We show that wild-type PfMDR1 transports erse pharmacons, including lumefantrine, mefloquine, dihydroartemisinin, piperaquine, amodiaquine, methylene blue, and chloroquine (but not the antiviral drug amantadine). Field-derived mutant isoforms of PfMDR1 differ from the wild-type protein, and each other, in their capacities to transport these drugs, indicating that PfMDR1-induced changes in the distribution of drugs between the parasite’s digestive vacuole (DV) and the cytosol are a key driver of both antimalarial resistance and the variability between multidrug resistance phenotypes. Of note, the PfMDR1 isoforms prevalent in chloroquine-resistant isolates exhibit reduced capacities for chloroquine, lumefantrine, and mefloquine transport. We observe the opposite relationship between chloroquine resistance-conferring mutations in PfCRT and drug transport activity. Using our established assays for characterizing PfCRT in the Xenopus oocyte system and in live parasite assays, we demonstrate that these PfCRT isoforms transport all 3 drugs, whereas wild-type PfCRT does not. We present a mechanistic model for collateral drug sensitivity in which mutant isoforms of PfMDR1 and PfCRT cause chloroquine, lumefantrine, and mefloquine to remain in the cytosol instead of sequestering within the DV. This change in drug distribution increases the access of lumefantrine and mefloquine to their primary targets (thought to be located outside of the DV), while simultaneously decreasing chloroquine’s access to its target within the DV. The mechanistic insights presented here provide a basis for developing approaches that extend the useful life span of antimalarials by exploiting the opposing selection forces they exert upon PfCRT and PfMDR1.
Computer Simulation of Ion Channels
Publisher: The Royal Society of Chemistry
Date: 05-12-2016
DOI: 10.1039/9781782626695-00161
Abstract: Ion channels provide a pathway for charged and polar solutes to cross cell membranes, thereby regulating the electrical excitability of cells and helping to initiate cellular responses. Computer simulations have been an important tool in understanding how this family of proteins work. In this chapter, we describe how simulations have been used to address issues such as how ions move through ion channels, how channels distinguish between ion types, how channels open and close in response to stimuli and how channels can be modulated by drugs and toxins. In doing so, we hope to demonstrate how different simulation approaches can be used to gain a mechanistic understanding of the function of this important protein family.
Electrostatic basis of valence selectivity in cationic channels
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.BBAMEM.2005.03.002
Abstract: We examine how a variety of cationic channels discriminate between ions of differing charge. We construct models of the KcsA potassium channel, voltage gated sodium channel and L-type calcium channel, and show that they all conduct monovalent cations, but that only the calcium channel conducts alent cations. In the KcsA and sodium channels alent ions block the channel and prevent any further conduction. We demonstrate that in each case, this discrimination and some of the more complex conductance properties of the channels is a consequence of the electrostatic interaction of the ions with the charges in the channel protein. The KcsA and sodium channels bind alent ions strongly enough that they cannot be displaced by other ions and thereby block the channel. On the other hand, the calcium channel binds them less strongly such that they can be destabilized by the repulsion of another incoming alent ion, but not by the lesser repulsion from monovalent ions.
Differences in local anaesthetic and antiepileptic binding in the inactivated state of human sodium channel Nav1.4
Publisher: Elsevier BV
Date: 12-2021
Designing Carbon Nanotube Membranes for Efficient Water Desalination
Publisher: American Chemical Society (ACS)
Date: 29-12-2007
DOI: 10.1021/JP709845U
Abstract: The transport of water and ions through membranes formed from carbon nanotubes ranging in diameter from 6 to 11 A is studied using molecular dynamics simulations under hydrostatic pressure and equilibrium conditions. Membranes incorporating carbon nanotubes are found to be promising candidates for water desalination using reverse osmosis, and the size and uniformity of tubes that is required to achieve a desired salt rejection is determined. By calculating the potential of mean force for ion and water translocation, we show that ions face a large energy barrier and will not pass through the narrower tubes studied ((5,5) and (6,6) "armchair" type tubes) but can pass through the wider (7,7) and (8,8) nanotubes. Water, however, faces no such impediment due to the formation of stable hydrogen bonds and crosses all of the tubes studied at very large rates. By measuring this conduction rate under a hydrostatic pressure difference, we show that membranes incorporating carbon nanotubes can, in principle, achieve a high degree of desalination at flow rates far in excess of existing membranes.
Permeation dynamics of chloride ions in the CIC-0 and CIC-1 channels
Publisher: Elsevier BV
Date: 03-2004
Structural Investigation of MscL Gating Using Experimental Data and Coarse Grained MD Simulations
Publisher: Public Library of Science (PLoS)
Date: 20-09-2012
Brownian dynamics study of flux ratios in sodium channels
Publisher: Springer Science and Business Media LLC
Date: 02-07-2008
DOI: 10.1007/S00249-008-0353-5
Abstract: Measurements of unidirectional fluxes in ion channels provide one of the experimental methods for studying the steps involved in ion permeation in biological pores. Conventionally, the number of ions in the pore is inferred by fitting the ratio of inward and outward currents to an exponential function with an adjustable parameter known as the flux ratio exponent. Here we investigate the relationship between the number of ions in the pore and the flux ratio exponent in a model sodium channel under a range of conditions. Brownian dynamics simulations enable us to count the precise number of ions in the channel and at the same time measure the currents flowing across the pore in both directions. We show here that the values of the flux ratio exponent n' ranges between 1 and 3 and is highly dependent on the ionic concentrations in which measurements are made. This is a consequence of the fact that both inward and outward currents are susceptible to saturation with increasing concentration. These results indicate that measurements of the flux ratio exponent cannot be directly related to the number of ions in the pore and that interpretation of such experimental measurements requires careful consideration of the conditions in which the study is made.
Ammoelphidiella from the Pliocene of Larsemann Hills, East Antarctica
Publisher: Cushman Foundation for Foraminiferal Research
Date: 1990
DOI: 10.2113/GSJFR.20.1.1
Conduction Properties of KcsA Measured Using Brownian Dynamics with Flexible Carbonyl Groups in the Selectivity Filter
Publisher: Elsevier BV
Date: 07-2007
Invalidity of continuum theories of electrolytes in nanopores
Publisher: Elsevier BV
Date: 03-2000
A binding site for phosphoinositide modulation of voltage-gated sodium channels described by multiscale simulations
Publisher: Cold Spring Harbor Laboratory
Date: 17-07-2023
DOI: 10.1101/2023.07.16.547149
Abstract: Voltage gated sodium channels (Na v ) are membrane proteins which open to facilitate the inward flux of sodium ions into excitable cells. In response to stimuli, Na v channels undergo a transition from the resting, closed state to an open state which allows ion influx, before rapidly inactivating. Dysregulation of this functional cycle due to mutations leads to diseases including epilepsy, pain conditions and cardiac disorders, making Na v channels a significant pharmacological target. Phosphoinositides are important lipid cofactors for ion channel function. The phosphoinositide PI(4,5)P 2 decreases Na v 1.4 activity by increasing the difficulty of channel opening, accelerating fast activation and slowing recovery from fast inactivation. Using multiscale molecular dynamics simulations, we show that PI(4,5)P 2 binds stably to inactivated Na v at a conserved site within the DIV S4-S5 linker, which couples the voltage sensing domain (VSD) to the pore. As the Na v C-terminal domain is proposed to also bind here during recovery from inactivation, we hypothesise that PI(4,5)P 2 prolongs inactivation by competing to bind to this site. In atomistic simulations, PI(4,5)P 2 reduces the mobility of both the DIV S4-S5 linker and the DIII-IV linker, responsible for fast inactivation, slowing the conformational changes required for the channel to recover to the resting state. We further show that in a resting state Na v model, phosphoinositides bind to VSD gating charges, which may anchor them and impede VSD activation. Our results provide a mechanism by which phosphoinositides alter the voltage dependence of activation and the rate of recovery from inactivation, an important step for the development of novel therapies to treat Na v -related diseases.
How does overcoordination create ion selectivity?
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.BPC.2012.11.005
Abstract: Some biological molecules can distinguish between ions of similar nature, which may be achieved by enforcing specific coordination numbers on ions in the binding site. It is suggested that when this number is favourable for one ion type, but too large for another, this creates ion selectivity through the proposed mechanism of 'overcoordination'. Much debate has occurred about the role overcoordination plays, and suggestions made as to how molecules can enforce particular coordination numbers, but there has not been an examination of the microscopic underpinning of ion selectivity by overcoordination. Here we use molecular-dynamics to systematically investigate how the number of ligands affects the ion-ligand and ligand-ligand interaction energies, and thus the thermodynamic ion selectivity, of a combination of model systems: three ions (Li(+)/Na(+)/K(+)) with three different ligands (water/formaldehyde/formamide). We find that the ligand-ligand repulsion controls the changes in geometry of each system with changing ligand number. Ion selectivity by overcoordination is achieved as smaller ions exhibit anomalous geometrical changes with the addition of extra ligands, whilst larger ions do not.
Pharmacological Insights and Quirks of Bacterial Sodium Channels
Publisher: Springer Berlin Heidelberg
Date: 2014
DOI: 10.1007/978-3-642-41588-3_12
Abstract: The pedigree of voltage-gated sodium channels spans the millennia from eukaryotic members that initiate the action potential firing in excitable tissues to primordial ancestors that act as enviro-protective complexes in bacterial extremophiles. Eukaryotic sodium channels (eNavs) are central to electrical signaling throughout the cardiovascular and nervous systems in animals and are established clinical targets for the therapeutic management of epilepsy, cardiac arrhythmia, and painful syndromes as they are inhibited by local anesthetic compounds. Alternatively, bacterial voltage-gated sodium channels (bNavs) likely regulate the survival response against extreme pH conditions, electrophiles, and hypo-osmotic shock and may represent a founder of the voltage-gated cation channel family. Despite apparent differences between eNav and bNav channel physiology, gating, and gene structure, the discovery that bNavs are amenable to crystallographic study opens the door for the possibility of structure-guided rational design of the next generation of therapeutics that target eNavs. Here we summarize the gating behavior of these disparate channel members and discuss mechanisms of local anesthetic inhibition in light of the growing number of bNav structures.
The role of thermodynamics and kinetics in ligand binding to G-quadruplex DNA
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2CC32240D
Abstract: Molecular dynamics simulations were used to investigate the binding of four different 2,4,6-triarylpyridines to G-quadruplex DNA. Both the binding free energies, and the kinetics of binding are required to explain the measured degree of ligand induced stabilisation of the compounds, with bulky substituents having the potential to prevent the ligand from reaching the lowest energy binding site.
TLR7 gain-of-function genetic variation causes human lupus
Publisher: Springer Science and Business Media LLC
Date: 27-04-2022
DOI: 10.1038/S41586-022-04642-Z
Abstract: Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease 1–7 , evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA 8 , 9 and binds to guanosine 10 – 12 . We identified a de novo, previously undescribed missense TLR7 Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7 Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP 10–12 , and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c + age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7 Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.
Catharine Macaulay’s enlightenment faith and radical politics
Publisher: Informa UK Limited
Date: 16-10-2018
Long Timescale Molecular Simulations for Understanding Ion Channel Function
Publisher: Wiley
Date: 24-09-2015
In pursuit of a selective hepatocellular carcinoma therapeutic agent: Novel thalidomide derivatives with antiproliferative, antimigratory and STAT3 inhibitory properties
Publisher: Elsevier BV
Date: 05-2021
Computational study of methyl group dynamics in the hydroquinone clathrate of acetonitrile
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2CP23384C
Abstract: We report molecular dynamics simulations of the acetonitrile clathrate of hydroquinone, with a focus on the dynamics of acetonitrile methyl groups. There are three inequivalent acetonitrile molecules in the unit cell, one with its dipole parallel to the c-axis, and the other two antiparallel. Although these three guest molecules have previously been found to exhibit two slightly different frequencies of rotation over a wide range of temperatures, the frequencies could not be assigned to specific methyl groups. Perhaps counterintuitively, our simulations suggest that the molecule with the lower frequency is one of the two molecules oriented the same way, the different dynamical behaviour being due to subtle differences in the environments of the molecules.
Modeling thermodiffusion in aqueous sodium chloride solutions—Which water model is best?
Publisher: AIP Publishing
Date: 26-04-2022
DOI: 10.1063/5.0088325
Abstract: Thermodiffusion is the migration of a species due to a temperature gradient and is the driving phenomenon in many applications ranging from early cancer detection to uranium enrichment. Molecular dynamics (MD) simulations can be a useful tool for exploring the rather complex thermodiffusive behavior of species, such as proteins and ions. However, current MD models of thermodiffusion in aqueous ionic solutions struggle to quantitatively predict the Soret coefficient, which indicates the magnitude and direction of species migration under a temperature gradient. In this work, we aim to improve the accuracy of MD thermodiffusion models by assessing how well different water models can recreate thermodiffusion in a benchmark aqueous NaCl solution. We tested four of the best available rigid non-polarizable water models (TIP3P-FB, TIP4P-FB, OPC3, and OPC) and the commonly used TIP3P and SPC/E water models for their ability to predict the inversion temperature and Soret coefficient in 0.5, 2, and 4M aqueous NaCl solutions. Each water model predicted a noticeably different ion distribution yielding different inversion temperatures and magnitudes of the Soret coefficient. By comparing the modeled Soret coefficients to published experimental values, we determine TIP3P-FB to be the water model that best recreates thermodiffusion in aqueous NaCl solutions. Our findings can aid future works in selecting the most accurate rigid non-polarizable water model, including water and ion parameters for investigating thermodiffusion through MD simulations.
Ion Conduction in Ligand-Gated Ion Channels: Brownian Dynamics Studies of Four Recent Crystal Structures
Publisher: Elsevier BV
Date: 02-2010
Mechanism of Ion Permeation and Selectivity in a Voltage Gated Sodium Channel
Publisher: American Chemical Society (ACS)
Date: 12-01-2012
DOI: 10.1021/JA210020H
Abstract: The rapid and selective transport of Na(+) through sodium channels is essential for initiating action potentials within excitable cells. However, an understanding of how these channels discriminate between different ion types and how ions permeate the pore has remained elusive. Using the recently published crystal structure of a prokaryotic sodium channel from Arcobacter butzleri, we are able to determine the steps involved in ion transport and to pinpoint the location and likely mechanism used to discriminate between Na(+) and K(+). Na(+) conduction is shown to involve the loosely coupled "knock-on" movement of two solvated ions. Selectivity arises due to the inability of K(+) to fit between a plane of glutamate residues with the preferred solvation geometry that involves water molecules bridging between the ion and carboxylate groups. These mechanisms are different to those described for K(+) channels, highlighting the importance of developing a separate mechanistic understanding of Na(+) and Ca(2+) channels.
Unraveling the relationship between structure and stabilization of triarylpyridines as G-quadruplex binding ligands
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1OB05560G
Abstract: A series of novel 2,4,6-triarylpyridines have been synthesized and their interactions with intramolecular G-quadruplexes have been measured by Förster Resonance Energy Transfer (FRET) melting and Fluorescent Intercalator Displacement (FID) assays. A few of these compounds exhibit stabilization of G4-DNA that is comparable to other benchmark G4-DNA ligands with fair to excellent G4-DNA vs. duplex selectivity and significant cytotoxicity towards HeLa cells. The nature of the 4-aryl substituents along with side chain length governs the G4-DNA stabilization ability of the compounds. In addition, we demonstrate that there is a strong correlation between the ability of the compounds to stabilize the same G4-DNA sequence in K(+) and Na(+) conditions and a strong correlation between the ability of the compounds to stabilize different G4-DNA sequences in K(+) or Na(+) buffer.
Tests of Continuum Theories as Models of Ion Channels. I. Poisson−Boltzmann Theory versus Brownian Dynamics
Publisher: Elsevier BV
Date: 05-2000
Computational methods and theory for ion channel research
Publisher: Informa UK Limited
Date: 17-06-2022
Determination of the Kinetic Profile of a Dinuclear Platinum Anticancer Complex in the Presence of Sulfate: Introducing a New Tool for the Expedited Analysis of 2D [1H, 15N] HSQC
Publisher: American Chemical Society (ACS)
Date: 10-11-2010
DOI: 10.1021/IC100576K
Diamond nanopillar arrays for quantum microscopy of neuronal signals
Publisher: SPIE-Intl Soc Optical Eng
Date: 06-08-2020
The naked truth about K+ selectivity
Publisher: Springer Science and Business Media LLC
Date: 20-07-2018
The Importance of Dehydration in Determining Ion Transport in Narrow Pores
Publisher: Wiley
Date: 21-03-2012
Abstract: The transport of hydrated ions through narrow pores is important for a number of processes such as the desalination and filtration of water and the conductance of ions through biological channels. Here, molecular dynamics simulations are used to systematically examine the transport of anionic drinking water contaminants (fluoride, chloride, nitrate, and nitrite) through pores ranging in effective radius from 2.8 to 6.5 Å to elucidate the role of hydration in excluding these species during nanofiltration. Bulk hydration properties (hydrated size and coordination number) are determined for comparison with the situations inside the pores. Free energy profiles for ion transport through the pores show energy barriers depend on pore size, ion type, and membrane surface charge and that the selectivity sequence can change depending on the pore size. Ion coordination numbers along the trajectory showed that partial dehydration of the transported ion is the main contribution to the energy barriers. Ion transport is greatly hindered when the effective pore radius is smaller than the hydrated radius, as the ion has to lose some associated water molecules to enter the pore. Small energy barriers are still observed when pore sizes are larger than the hydrated radius due to re-orientation of the hydration shell or the loss of more distant water. These results demonstrate the importance of ion dehydration in transport through narrow pores, which increases the current level of mechanistic understanding of membrane-based desalination and transport in biological channels.
Solvent Transport Behavior of Shear Aligned Graphene Oxide Membranes and Implications in Organic Solvent Nanofiltration
Publisher: American Chemical Society (ACS)
Date: 03-01-2018
Abstract: Solvent transport in membranes composed of stacked sheets of graphene oxide (GO) with molecular scale channels and a complex arrangement of hydrophobic and hydrophilic domains is not well understood. Here, we observe that the interlayer space between GO sheets expands in different solvents without disturbing the membrane integrity and is typically larger in aqueous media compared to nonaqueous media. However, the membranes have a tighter molecule sieving feature in aqueous media as demonstrated by lower permeance and higher solute rejection arising from interfacial water layers "sticking" to charged polar groups. As a result of this polar interaction, the permeance of polar solvents in GO membrane scales inversely to the polarity of the solvent, which is contrary to other polymeric and ceramic hydrophilic membranes and also scales inversely to the viscosity of solvents as per continuum expectations. We highlight the extended solvent-handling space of GO membranes, such as in polar protic, polar aprotic, and nonpolar solvents, demonstrating versatility over a commercial nanofiltration membrane, and we predict exciting new applications in advanced separation engineering.
Selective IgA deficiency in early life: Association to infections and allergic diseases during childhood
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.CLIM.2009.05.014
Abstract: Selective IgA deficiency in early life is quite common in Caucasian populations, but it is unclear whether it increases the risk of infections and allergic diseases during childhood. Serum IgA levels were measured in 2423 children at 4 years of age in a Swedish population based birth cohort (BAMSE). Parental questionnaires were repeatedly sent out during the child's first 8 years of life, collecting information about infections and allergic diseases. 14 children (1:173) were found to be IgA deficient at 4 years of age. These children had an increased risk of pseudocroup at year 1 (p<0.01) and food hypersensitivity at year 4 (p<0.05) as compared to IgA sufficient children. No increased risk was observed in the partial IgA deficiency group. The findings suggest that selective IgA deficiency may increase the risk of parentally reported pseudocroup and food hypersensitivity during early childhood.
Nanostructured carbon membranes for breakthrough filtration applications: advancing the science, engineering and design
Publisher: The Royal Society
Date: 13-02-2016
Three computational methods for studying permeation, selectivity and dynamics in biological ion channels
Publisher: Royal Society of Chemistry (RSC)
Date: 2005
DOI: 10.1039/B512455G
A functional correlate of severity in alternating hemiplegia of childhood.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.NBD.2015.02.002
Abstract: Mutations in ATP1A3, the gene that encodes the α3 subunit of the Na(+)/K(+) ATPase, are the primary cause of alternating hemiplegia of childhood (AHC). Correlations between different mutations and AHC severity were recently reported, with E815K identified in severe and D801N and G947R in milder cases. This study aims to explore the molecular pathological mechanisms in AHC and to identify functional correlates for mutations associated with different levels of disease severity. Human wild type ATP1A3, and E815K, D801N and G947R mutants were expressed in Xenopus laevis oocytes and Na(+)/K(+) ATPase function measured. Structural homology models of the human α3 subunit containing AHC mutations were created. The AHC mutations examined all showed similar levels of reduction in forward cycling. Wild type forward cycling was reduced by coexpression with any mutant, indicating dominant negative interactions. Proton transport was measured and found to be selectively impaired only in E815K. Homology modeling showed that D801 and G947 lie within or near known cation binding sites while E815 is more distal. Despite its effect on proton transport, E815K was also distant from the proposed proton transport route. Loss of forward cycling and dominant negativity are common and likely necessary pathomechanisms for AHC. In addition, loss of proton transport correlated with severity of AHC. D801N and G947R are likely to directly disrupt normal Na(+)/K(+) binding while E815K may disrupt forward cycling and proton transport via allosteric mechanisms yet to be elucidated.
A Cytosolic Granzyme B Inhibitor Related to the Viral Apoptotic Regulator Cytokine Response Modifier A Is Present in Cytotoxic Lymphocytes
Publisher: Elsevier BV
Date: 11-1996
FRET-Modulated Multihybrid Nanoparticles for Brightness-Equalized Single-Wavelength Barcoding
Publisher: American Chemical Society (ACS)
Date: 18-06-2019
DOI: 10.1021/JACS.9B03383
Abstract: Semiconductor quantum dots (QDs) are the most versatile fluorophores for Förster resonance energy transfer (FRET) because they can function as both donors and acceptors for a multitude of fluorophores. However, a complete understanding of multidonor-multiacceptor FRET networks on QDs and their full employment into advanced fluorescence sensing and imaging have not been accomplished. Here, we provide a holistic photophysical analysis of such multidonor-QD-multiacceptor FRET systems using time-resolved and steady-state photoluminescence (PL) spectroscopy and Monte Carlo simulations. Multiple terbium complex (Tb) donors (1-191 units) and Cy5.5 dye acceptors (1-60 units) were attached to a central QD, and the entire range of combinations of FRET pathways was investigated by Tb, QD, and Cy5.5 PL. Experimental and simulation results were in excellent agreement and could disentangle the distinct contributions of hetero-FRET, homo-FRET, and dye dimerization. The FRET efficiency was independent of the number of Tb donors and dependent on the number of Cy5.5 acceptors, which could be used to independently adapt the PL intensity by the number of Tb donors and the PL lifetime by the number of Cy5.5 acceptors. We used this unique tuning capability to prepare Tb-QD-Cy5.5 conjugates with distinct QD PL lifetimes but similar QD PL intensities. These brightness-equalized multihybrid FRET nanoparticles were applied to optical barcoding via three time-gated PL intensity detection windows, which resulted in simple RGB ratios. Direct applicability was demonstrated by an efficient RGB distinction of different nanoparticle-encoded microbeads within the same field of view with both single-wavelength excitation and detection on a standard fluorescence microscope.
Water and ion transport through functionalised carbon nanotubes: implications for desalination technology
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0EE00481B
A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin
Publisher: Springer Science and Business Media LLC
Date: 30-09-2022
DOI: 10.1038/S41467-022-33403-9
Abstract: Diverse compounds target the Plasmodium falciparum Na + pump PfATP4, with cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4 G358S parasites can withstand micromolar concentrations of cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in Toxoplasma gondii ATP4, decrease the sensitivity of ATP4 to inhibition by cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na + regulation. The G358S mutation reduces the affinity of PfATP4 for Na + and is associated with an increase in the parasite’s resting cytosolic [Na + ]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4 G358S parasites, and that their combination with unrelated antimalarials may mitigate against resistance development.
Voltage-Gated Sodium Channel Pharmacology: Insights From Molecular Dynamics Simulations
Publisher: Elsevier
Date: 2017
DOI: 10.1016/BS.APHA.2017.02.002
Abstract: Voltage-gated ion channels are the target of a range of naturally occurring toxins and therapeutic drugs. There is a great interest in better understanding how these erse compounds alter channel function in order to design the next generation of therapeutics that can selectively target one of the channel subtypes found in the body. Since the publication of a number of bacterial sodium channel structures, molecular dynamics simulations have been invaluable in gaining a high resolution understanding where many of these small molecules and toxins bind to the channels, how they find their binding site, and how they can selectively bind to one channel subtype over another. This chapter summarizes these recent studies to highlight what has been learnt about channel pharmacology using computer simulations and to draw out shared conclusions, focusing separately on toxin-channel interactions and small molecule-channel interactions.
Biological Channeling of a Reactive Intermediate in the Bifunctional Enzyme DmpFG
Publisher: Elsevier BV
Date: 02-2012
Comparing the Ability of Enhanced Sampling Molecular Dynamics Methods To Reproduce the Behavior of Fluorescent Labels on Proteins
Publisher: American Chemical Society (ACS)
Date: 16-06-2015
Abstract: Adequately s ling the large number of conformations accessible to proteins and other macromolecules is one of the central challenges in molecular dynamics (MD) simulations this activity can be difficult, even for relatively simple systems. An ex le where this problem arises is in the simulation of dye-labeled proteins, which are now being widely used in the design and interpretation of Förster resonance energy transfer (FRET) experiments. In this study, MD simulations are used to characterize the motion of two commonly used FRET dyes attached to an immobilized chain of polyproline. Even in this simple system, the dyes exhibit complex behavior that is a mixture of fast and slow motions. Consequently, very long MD simulations are required to sufficiently s le the entire range of dye motion. Here, we compare the ability of enhanced s ling methods to reproduce the behavior of fluorescent labels on proteins. In particular, we compared Accelerated Molecular Dynamics (AMD), metadynamics, Replica Exchange Molecular Dynamics (REMD), and High Temperature Molecular Dynamics (HTMD) to equilibrium MD simulations. We find that, in our system, all of these methods improve the s ling of the dye motion, but the most significant improvement is achieved using REMD.
Ice-like water structure in carbon nanotube (8,8) induces cationic hydration enhancement
Publisher: American Chemical Society (ACS)
Date: 16-05-2013
DOI: 10.1021/JP4025206
Thermostat choice significantly influences water flow rates in molecular dynamics studies of carbon nanotubes
Publisher: Springer Science and Business Media LLC
Date: 03-05-2014
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