ORCID Profile
0000-0002-1099-2803
Current Organisation
University of Wollongong
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Materials Engineering | Composite and Hybrid Materials | Materials Engineering not elsewhere classified | Nanomaterials | Turbulent Flows | Functional Materials | Theoretical and Computational Chemistry not elsewhere classified | Biomolecular Modelling and Design | Biochemistry and Cell Biology | Quantum Chemistry | Interdisciplinary Engineering | Nanophotonics | Structural Biology (incl. Macromolecular Modelling)
Hydrogen-based Energy Systems (incl. Internal Hydrogen Combustion Engines) | Environmentally Sustainable Energy Activities not elsewhere classified | Hydrogen Storage | Education and Training not elsewhere classified | Information and Communication Services not elsewhere classified | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Information and Computing Sciences | Expanding Knowledge in the Biological Sciences |
Publisher: American Chemical Society (ACS)
Date: 16-02-2021
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier
Date: 2017
DOI: 10.1016/BS.APCSB.2017.04.003
Abstract: Carbohydrate-active enzymes (CAZymes) are families of essential and structurally related enzymes, which catalyze the creation, modification, and degradation of glycosidic bonds in carbohydrates to maintain essentially all kingdoms of life. CAZymes play a key role in many biological processes underpinning human health and diseases (e.g., cancer, diabetes, Alzheimer's diseases, AIDS) and have thus emerged as important drug targets in the fight against pathogenesis. The realization of the full potential of CAZymes remains a significant challenge, relying on a deeper understanding of the molecular mechanisms of catalysis. Considering numerous unsettled questions in the literature, while with a large amount of structural, kinetic, and mutagenesis data available for CAZymes, there is a pressing need and an abundant opportunity for collaborative computational and experimental investigations with the aim to unlock the secrets of CAZyme catalysis at an atomic level. In this review, we briefly survey key methodology development in computational studies of CAZyme catalysis. This is complemented by selected case studies highlighting mechanistic insights provided by computational glycobiology. Implication for inhibitor design by mimicking the transition state is also illustrated for both glycoside hydrolases and glycosyltransferases. The challenges for such studies will be noted and finally an outlook for future directions will be provided.
Publisher: Wiley
Date: 26-06-2019
Publisher: AIP Publishing
Date: 09-2021
DOI: 10.1063/4.0000124
Abstract: Here we report the vibrational spectra of deprotonated serine calculated from the classical molecular dynamics (MD) simulations and thermostated ring-polymer molecular dynamics (TRPMD) simulation with third-order density-functional tight-binding. In our earlier study [Inakollu and Yu, “A systematic benchmarking of computational vibrational spectroscopy with DFTB3: Normal mode analysis and fast Fourier transform dipole autocorrelation function,” J. Comput. Chem. 39, 2067 (2018)] of deprotonated serine, we observed a significant difference in the vibrational spectra with the classical MD simulations compared to the infrared multiple photon dissociation spectra. It was postulated that this is due to neglecting the nuclear quantum effects (NQEs). In this work, NQEs are considered in spectral calculation using the TRPMD simulations. With the help of potential of mean force calculations, the conformational space of deprotonated serine is analyzed and used to understand the difference in the spectra of classical MD and TRPMD simulations at 298.15 and 100 K. The high-frequency vibrational bands in the spectra are characterized using Fourier transform localized vibrational mode (FT-νNAC) and interatomic distance histograms. At room temperature, the quantum effects are less significant, and the free energy profiles in the classical MD and the TRPMD simulations are very similar. However, the hydrogen bond between the hydroxyl–carboxyl bond is slightly stronger in TRPMD simulations. At 100 K, the quantum effects are more prominent, especially in the 2600–3600 cm−1, and the free energy profile slightly differs between the classical MD and TRPMD simulations. Using the FT-νNAC and the interatomic distance histograms, the high-frequency vibrational bands are discussed in detail.
Publisher: Springer Science and Business Media LLC
Date: 26-09-2022
DOI: 10.1038/S41467-022-33090-6
Abstract: The Redβ protein of the bacteriophage λ red recombination system is a model annealase which catalyzes single-strand annealing homologous DNA recombination. Here we present the structure of a helical oligomeric annealing intermediate of Redβ, consisting of N-terminal residues 1-177 bound to two complementary 27mer oligonucleotides, determined via cryogenic electron microscopy (cryo-EM) to a final resolution of 3.3 Å. The structure reveals a continuous binding groove which positions and stabilizes complementary DNA strands in a planar orientation to facilitate base pairing via a network of hydrogen bonding. Definition of the inter-subunit interface provides a structural basis for the propensity of Redβ to oligomerize into functionally significant long helical filaments, a trait shared by most annealases. Our cryo-EM structure and molecular dynamics simulations suggest that residues 133-138 form a flexible loop which modulates access to the binding groove. More than half a century after its discovery, this combination of structural and computational observations has allowed us to propose molecular mechanisms for the actions of the model annealase Redβ, a defining member of the Redβ/RecT protein family.
Publisher: Cambridge University Press (CUP)
Date: 03-08-2021
DOI: 10.33774/CHEMRXIV-2021-B5C49
Abstract: Here we report the vibrational spectra of deprotonated serine calculated from the classical molecular dynamics (MD) simulations and thermostated ring-polymer molecular dynamics (TRPMD) simulation with DFTB3. In our earlier study1 of deprotonated serine, we observed a significant difference in the vibrational spectra with the classical MD simulations compared to the infrared multiple photon dissociation (IRMPD) spectra. It was postulated that this is due to neglecting the nuclear quantum effects (NQEs). In this work, NQEs are considered in the spectral calculation using the TRPMD simulations. With the help of potential of mean force (PMF) calculations, the conformational space of deprotonated serine is analysed and used to understand the difference in the spectra of classical MD and TRPMD simulations at 298.15 K and 100 K. The high-frequency vibrational bands in the spectra are characterised using Fourier transform localised vibrational mode (FT-νNAC) and interatomic distance histograms. At room temperature, the quantum effects are less significant, and the free energy profiles in the classical MD and the TRPMD simulations are very similar. However, the hydrogen bond between the hydroxyl-carboxyl bond is slightly stronger in TRPMD simulations. At 100 K, the quantum effects are more prominent, especially in the 2600-3600 cm−1, and the free energy profile slightly differs between the classical MD and TRPMD simulations. Using the FT-νNAC and the interatomic distance histograms, the high-frequency vibrational bands are discussed in detail.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.JMGM.2015.01.001
Abstract: The nsP2 protease of chikungunya virus (CHIKV) is one of the essential components of viral replication and it plays a crucial role in the cleavage of polyprotein precursors for the viral replication process. Therefore, it is gaining attention as a potential drug design target against CHIKV. Based on the recently determined crystal structure of the nsP2 protease of CHIKV, this study identified potential inhibitors of the virus using structure-based approaches with a combination of molecular docking, virtual screening and molecular dynamics (MD) simulations. The top hit compounds from database searching, using the NCI Diversity Set II, with targeting at five potential binding sites of the nsP2 protease, were identified by blind dockings and focused dockings. These complexes were then subjected to MD simulations to investigate the stability and flexibility of the complexes and to gain a more detailed insight into the interactions between the compounds and the enzyme. The hydrogen bonds and hydrophobic contacts were characterized for the complexes. Through structural alignment, the catalytic residues Cys1013 and His1083 were identified in the N-terminal region of the nsP2 protease. The absolute binding free energies were estimated by the linear interaction energy approach and compared with the binding affinities predicted with docking. The results provide valuable information for the development of inhibitors for CHIKV.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4CP00351A
Abstract: Glycoside hydrolase families 33 and 34 catalyse the hydrolysis of terminal sialic acid residues from sialyl oligosaccharides and glycoconjugates with a net retention of the stereochemistry at the anomeric centre. It is generally believed that the conserved aspartic acid in the active site functions as a general acid to protonate the hydroxyl group of the departing aglycone during glycosylation, and then as a general base to facilitate the nucleophilic attack of the water molecule on the intermediate state during the deglycosylation reaction. The dual role of the general acid/base places specific demands upon its protonation state, and thus pKa values. However, it is not fully understood how this catalytic residue can achieve such pKa cycling during catalysis. We present both MM and combined QM/MM simulations to characterise the pKa values of the proposed catalytic general acid/base in the glycoside hydrolase families 33 and 34. Collectively, our study suggests that the binding of anionic substrates and the local solvation properties along with the neutralisation of the nearby glutamic acid upon glycosylation modulate the electrostatic environment around the general acid/base to achieve its proper protonation states.
Publisher: Elsevier BV
Date: 09-2008
Publisher: AIP Publishing
Date: 19-12-2007
DOI: 10.1063/1.2806992
Abstract: Proton transfers are involved in many chemical processes in solution and in biological systems. Although water molecules have been known to transiently facilitate proton transfers, the possibility that water molecules may serve as the “storage site” for proton in biological systems has only been raised in recent years. To characterize the structural and possibly the dynamic nature of these protonated water clusters, it is important to use effective computational techniques to properly interpret experimental spectroscopic measurements of condensed phase systems. Bearing this goal in mind, we systematically benchmark the self-consistent-charge density-functional tight-binding (SCC-DFTB) method for the description of vibrational spectra of protonated water clusters in the gas phase, which became available only recently with infrared multiphoton photodissociation and infrared predissociation spectroscopic experiments. It is found that SCC-DFTB qualitatively reproduces the important features in the vibrational spectra of protonated water clusters, especially concerning the characteristic signatures of clusters of various sizes. In agreement with recent ab initio molecular dynamics studies, it is found that dynamical effects play an important role in determining the vibrational properties of these water clusters. Considering computational efficiency, these benchmark calculations suggest that the SCC-DFTB/molecular mechanical approach can be an effective tool for probing the structural and dynamic features of protonated water molecules in biomolecular systems.
Publisher: American Chemical Society (ACS)
Date: 03-08-2021
Publisher: CSIRO Publishing
Date: 2012
DOI: 10.1071/CH12026
Abstract: The sodium–potassium (Na/K) pump plays an essential role in maintaining cell volume and secondary active transport of other solutes by establishing the Na+ and K+ concentration gradients across the plasma membrane of animal cells. The recently determined crystal structures of the Na/K pump to atomic resolution provide a new impetus to investigate molecular determinants governing the binding of Na+ and K+ ions and conformational transitions during the functional cycle. The pump cycle is generally described by the alternating access mechanism, in which the pump toggles between different conformational states, where ions can bind from either the intracellular or the extracellular side. However, important issues concerning the selectivity of the Na/K pump remain to be addressed. In particular, two out of the three binding sites are shared between Na+ and K+ and it is not clear how the protein is able to select K+ over Na+ when it is in the outwardly facing phosphorylated conformation (E2P), and Na+ over K+ when it is in the inwardly facing conformation (E1). In this review article, we will first briefly review the recent advancement in understanding the microscopic mechanism of K+ selectivity in the Na/K pump at the E2·Pi state and then outline the remaining challenges to be addressed about ion selectivity.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Wiley
Date: 12-07-2006
DOI: 10.1002/JCC.20429
Abstract: A polarizable model for simulation of liquid methanol, compatible with the COS/G2 water model, has been developed using the Charge-on-Spring (COS) technique. The model consists of three point charges, with one polarizable center on the oxygen atom. The Lennard-Jones parameters on the oxygen atom together with the molecular polarizability were varied to reproduce the experimental heat of vaporization and density of liquid methanol at ambient conditions. We examined the energies of various methanol dimers in the gas phase and compared them with values obtained from ab initio calculations. The model was then used to study the thermodynamic, dynamic, structural, and dielectric properties of liquid methanol as well as of a methanol-water mixture. A microscopic picture of the structure of pure liquid methanol and of the methanol-water mixture is provided. Good agreement was found between the results from our model simulations and available experimental and ab initio calculation data. In particular, the experimental dielectric permittivity of 32 could be reproduced, which had been shown to be difficult when using nonpolarizable models.
Publisher: AIP Publishing
Date: 04-11-2004
DOI: 10.1063/1.1805516
Abstract: The properties of two improved versions of charge-on-spring (COS) polarizable water models (COS/G2 and COS/G3) that explicitly include nonadditive polarization effects are reported. In COS models, the polarization is represented via a self-consistently induced dipole moment consisting of a pair of separated charges. A previous polarizable water model (COS/B2), upon which the improved versions are based, was developed by Yu, Hansson, and van Gunsteren [J. Chem. Phys. 118, 221 (2003)]. To improve the COS/B2 model, which overestimated the dielectric permittivity, one additional virtual atomic site was used to reproduce the water monomer quadrupole moments besides the water monomer dipole moment in the gas phase. The molecular polarizability, residing on the virtual atomic site, and Lennard-Jones parameters for oxygen-oxygen interactions were varied to reproduce the experimental values for the heat of vaporization and the density of liquid water at room temperature and pressure. The improved models were used to study the properties of liquid water at various thermodynamic states as well as gaseous water clusters and ice. Overall, good agreement is obtained between simulated properties and those derived from experiments and ab initio calculations. The COS/G2 and COS/G3 models may serve as simple, classical, rigid, polarizable water models for the study of organic solutes and biopolymers. Due to its simplicity, COS type of polarization can straightforwardly be used to introduce explicit polarization into (bio)molecular force fields.
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.BCP.2019.113782
Abstract: Urotoxin (α-KTx 6), a peptide from venom of the Australian scorpion Urodacus yaschenkoi, is the most potent inhibitor of Kv1.2 described to date (IC
Publisher: Wiley
Date: 08-06-2006
Abstract: Computation based on molecular models is playing an increasingly important role in biology, biological chemistry, and biophysics. Since only a very limited number of properties of biomolecular systems is actually accessible to measurement by experimental means, computer simulation can complement experiment by providing not only averages, but also distributions and time series of any definable quantity, for ex le, conformational distributions or interactions between parts of systems. Present day biomolecular modeling is limited in its application by four main problems: 1) the force-field problem, 2) the search (s ling) problem, 3) the ensemble (s ling) problem, and 4) the experimental problem. These four problems are discussed and illustrated by practical ex les. Perspectives are also outlined for pushing forward the limitations of biomolecular modeling.
Publisher: Wiley
Date: 30-09-2018
DOI: 10.1002/JCC.25390
Abstract: Computational vibrational spectroscopy serves as an important tool in the interpretation of experimental infrared (IR) spectra. In this article, we present a systematic benchmarking study of DFTB3 with two different computational vibrational spectroscopic methods, based on either normal mode analysis (NMA) or fast Fourier transform dipole autocorrelation function (FT-DAC). The results were compared with experimental data and theoretical calculations with B3LYP/cc-pVTZ. The empirical scaling factors for DFTB3/NMA, DFTB3-freq/NMA, and DFTB3/FT-DAC methods are 0.9993, 1.0059, and 0.9982, respectively. We also demonstrate the significance of anharmonicity and conformational s ling in vibrational spectroscopic calculations on flexible molecules. As expected, DFTB3/FT-DAC predicted the anharmonic vibrational peaks more accurately than DFTB3/NMA and NMA spectra are highly dependent on the initial structures. The potential limitations of DFTB3 for vibrational spectroscopic calculations and the challenges in assigning the FT-DAC spectral peaks were noted. DFTB3/FT-DAC is expected to serve as a promising technique in computational spectroscopy in complex biomolecular systems. © 2018 Wiley Periodicals, Inc.
Publisher: Elsevier BV
Date: 02-2008
Publisher: Wiley
Date: 16-07-2020
DOI: 10.1002/POC.4110
Publisher: AIP Publishing
Date: 15-06-2010
DOI: 10.1063/1.3436632
Abstract: Quasichemical theory (QCT) provides a framework that can be used to partition the influence of the solvent surrounding an ion into near and distant contributions. Within QCT, the solvation properties of the ion are expressed as a sum of configurational integrals comprising only the ion and a small number of solvent molecules. QCT adopts a particularly simple form if it is assumed that the clusters undergo only small thermal fluctuations around a well-defined energy minimum and are affected exclusively in a mean-field sense by the surrounding bulk solvent. The fluctuations can then be integrated out via a simple vibrational analysis, leading to a closed-form expression for the solvation free energy of the ion. This constitutes the primitive form of quasichemical theory (pQCT), which is an approximate mathematical formulation aimed at reproducing the results from the full many-body configurational averages of statistical mechanics. While the results from pQCT from previous applications are reasonable, the accuracy of the approach has not been fully characterized and its range of validity remains unclear. Here, a direct test of pQCT for a set of ion models is carried out by comparing with the results of free energy simulations with explicit solvent. The influence of the distant surrounding bulk on the cluster comprising the ion and the nearest solvent molecule is treated both with a continuum dielectric approximation and with free energy perturbation molecular dynamics simulations with explicit solvent. The analysis shows that pQCT can provide an accurate framework in the case of a small cation such as Li+. However, the approximation encounters increasing difficulties when applied to larger cations such as Na+, and particularly for K+. This suggests that results from pQCT should be interpreted with caution when comparing ions of different sizes.
Publisher: American Chemical Society (ACS)
Date: 23-01-2018
Publisher: Wiley
Date: 16-12-2020
DOI: 10.1002/JCC.26125
Abstract: Bioluminescence in marine systems is dominated by the use of coelenterazine for light production. The bioluminescent reaction of coelenterazine is an enzyme catalyzed oxidative decarboxylation: coelenterazine reacts with molecular oxygen to form carbon dioxide, coelenteramide, and light. One such class is the Ca
Publisher: Springer Science and Business Media LLC
Date: 11-03-2018
DOI: 10.1007/S12539-016-0209-0
Abstract: The chikungunya virus (CHIKV) envelope glycoproteins are considered important potential targets for anti-CHIKV drug discovery due to their crucial roles in virus attachment and virus entry. In this study, using two available crystal structures of the immature and mature forms of envelope glycoproteins, virtual screenings based on blind dockings and focused dockings were carried out to identify potential binding pockets and hit compounds for the virus. The chemical library database of compounds, NCI Diversity Set II, was used in these docking studies. In addition to reproducing previously reported ex les, new binding pockets were identified, e.g., Pocket 2 in the 3N40, and Pocket 2 and Pocket 3 in the 3N42. Convergences in conformational s ling in docking using AutoDock Vina were evaluated. An analysis of docking results was carried out to understand interactions of the envelope glycoproteins complexes. Some key residues for interactions, for ex le Gly91 and His230, are identified as possessing important roles in the fusion process.
Publisher: Cambridge University Press (CUP)
Date: 10-08-2021
DOI: 10.33774/CHEMRXIV-2021-C6LRQ-V2
Abstract: The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising anti-metastasis target. 6-Substituted analogs of 5-N,N-(hexamethylene)amiloride (HMA) are potent and selective uPA inhibitors that lack the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. Here, computational and experimental findings reveal that residue 99 is a key contributor to the observed species selectivity, whereby enthalpically unfavorable expulsion of a water molecule by the 5-N,N-hexamethylene ring occurs when residue 99 is Tyr (as in mouse uPA). Analog 7 lacking the 5-N,N-hexamethylene ring maintained similar water networks when bound to human and mouse uPA and displayed reduced selectivity, thus supporting this conclusion. The study will guide further optimization of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.
Publisher: Cambridge University Press (CUP)
Date: 04-10-2021
DOI: 10.33774/CHEMRXIV-2021-C6LRQ-V3
Abstract: The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising anti-metastasis target. 6-Substituted analogs of 5-N,N-(hexamethylene)amiloride (HMA) are potent and selective uPA inhibitors that lack the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. Here, computational and experimental findings reveal that residue 99 is a key contributor to the observed species selectivity, whereby enthalpically unfavorable expulsion of a water molecule by the 5-N,N-hexamethylene ring occurs when residue 99 is Tyr (as in mouse uPA). Analog 7 lacking the 5-N,N-hexamethylene ring maintained similar water networks when bound to human and mouse uPA and displayed reduced selectivity, thus supporting this conclusion. The study will guide further optimization of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.
Publisher: Wiley
Date: 09-11-2018
DOI: 10.1002/JMR.2684
Abstract: Sialyltransferase (ST) upregulation and the resultant hypersialylation of tumour cell surfaces is an established hallmark of many cancers including lung, breast, ovarian, pancreatic and prostate cancer. The role of ST enzymes in tumour cell growth and metastasis, as well as links to multi-drug resistance, has seen ST inhibition emerge as a target for potential antimetastatic cancer treatments. The most potent of these reported inhibitors are transition-state analogues. Although there are several ex les of these in the literature, many have suspected poor pharmacokinetic properties and are not readily synthetically accessible. A proposed solution to these problems is the use of a neutral carbamate or 1,2,3-triazole linker instead of the more commonly used phosphodiester linker, and replacing the traditionally utilised cytidine nucleotide with uridine. Another issue in this area is the paucity of structural information of human ST enzymes. However, in late 2015 the structure of human ST8Sia III was reported (only the second human ST described so far), creating the opportunity for structure-based design of selective ST8 inhibitors for the first time. Herein, molecular docking and molecular dynamics simulations with the newly published crystal structure of hST8Sia III were performed for the first time with selected ST transition state analogues. Simulations showed that these compounds could participate in many of the key interactions common with the natural donor and acceptor substrates, and reveals some key insights into the synthesis of potentially selective ST inhibitors.
Publisher: Wiley
Date: 12-04-2021
Abstract: Amine–borane complexes have been extensively studied as hydrogen storage materials. Herein, we report a new amine–borane system featuring a reversible dehydrogenation and regeneration at room temperature. In addition to high purity H 2 , the reaction between ethylenediamine bisborane (EDAB) and ethylenediamine (ED) leads to unique boron–carbon–nitrogen 5‐membered rings in the dehydrogenation product where one boron is tricoordinated by three nitrogen atoms. Owing to the unique cyclic structure, the dehydrogenation product can be efficiently converted back to EDAB by NaBH 4 and H 2 O at room temperature. This finding could lead to the discovery of new amine boranes with potential usage as hydrogen storage materials.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0DT00319K
Abstract: A new nickel Schiff base complex shows selective binding behaviour towards quadruplex DNA and cytotoxicity against cancer cells.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-11-2010
Abstract: A theoretical framework is presented to clarify the molecular determinants of ion selectivity in protein binding sites. The relative free energy of a bound ion is expressed in terms of the main coordinating ligands coupled to an effective potential of mean force representing the influence of the rest of the protein. The latter is separated into two main contributions. The first includes all the forces keeping the ion and the coordinating ligands confined to a microscopic subvolume but does not prevent the ligands from adapting to a smaller or larger ion. The second regroups all the remaining forces that control the precise geometry of the coordinating ligands best adapted to a given ion. The theoretical framework makes it possible to delineate two important limiting cases. In the limit where the geometric forces are dominant (rigid binding site), ion selectivity is controlled by the ion-ligand interactions within the matching cavity size according to the familiar “snug-fit” mechanism of host-guest chemistry. In the limit where the geometric forces are negligible, the ion and ligands behave as a “confined microdroplet” that is free to fluctuate and adapt to ions of different sizes. In this case, ion selectivity is set by the interplay between ion-ligand and ligand-ligand interactions and is controlled by the number and the chemical type of ion-coordinating ligands. The framework is illustrated by considering the ion-selective binding sites in the KcsA channel and the LeuT transporter.
Publisher: Elsevier BV
Date: 07-2004
Publisher: Wiley
Date: 14-12-2019
Abstract: Electrochemical water splitting for hydrogen generation is a vital part for the prospect of future energy systems, however, the practical utilization relies on the development of highly active and earth-abundant catalysts to boost the energy conversion efficiency as well as reduce the cost. Molybdenum diselenide (MoSe
Publisher: Springer Science and Business Media LLC
Date: 23-10-2018
DOI: 10.1007/S00894-018-3863-9
Abstract: Density functional theory calculations were carried out to investigate the formation mechanism of the thymine-thymine (6-4) dimer ((6-4)TT), which is one of the main DNA lesions induced by ultraviolet radiation and is closely related to skin cancers. The DNA backbone was found to have nonnegligible effects on the triplet reaction pathway, particularly the reaction steps involving substantial base rotations. The mechanism for the isomerization from (6-4)TT to its Dewar valence isomer (DewarTT) was also explored, confirming the necessity of absorbing a second photon. In addition, the solvation effects were examined and showed considerable influence on the potential energy surface. Graphical Abstract DFT calculations on the influence of DNA backbone on the mechanism of UV-induced thymine-thymine (6-4) dimer formation.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Wiley
Date: 12-04-2021
Abstract: Amine–borane complexes have been extensively studied as hydrogen storage materials. Herein, we report a new amine–borane system featuring a reversible dehydrogenation and regeneration at room temperature. In addition to high purity H 2 , the reaction between ethylenediamine bisborane (EDAB) and ethylenediamine (ED) leads to unique boron–carbon–nitrogen 5‐membered rings in the dehydrogenation product where one boron is tricoordinated by three nitrogen atoms. Owing to the unique cyclic structure, the dehydrogenation product can be efficiently converted back to EDAB by NaBH 4 and H 2 O at room temperature. This finding could lead to the discovery of new amine boranes with potential usage as hydrogen storage materials.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6CP02526A
Abstract: Molecular mechanism for p K a shifts for the key residues in wild-type and mutants of BcX based on three different computational methods.
Publisher: Wiley
Date: 31-08-2006
DOI: 10.1002/PROT.20991
Abstract: Two designed ankyrin repeat (AR) proteins (E3_5 and E3_19) are high homologous (with about 87% sequence identity) and their crystal structures have a Calpha atom-positional root-mean-square difference of about 0.14 nm. However, it was found that E3_5 is considerably more stable than E3_19 in guanidinium hydrochloride and thermal denaturation experiments. With the goal of providing insights into the various factors contributing to the stabilities of the designed AR proteins and suggesting possible mutations to enhance their stabilities, homology modeling and molecular dynamics (MD) simulations with explicit solvent have been performed. Because the crystal structure of E3_19 was solved later than that of E3_5, a homology model of E3_19 based on the crystal structure of E3_5 was also used in the simulations. E3_5 shows a very stable trajectory in both crystal and solution simulations. In contrast, the C-terminal repeat of E3_19 unfolds in the simulations starting from either the modeled structure or the crystal structure, although it has a sequence identical to that of E3_5. A continuum electrostatic model was used to estimate the effect of single mutations on protein stability and to study the interaction between the internal ARs and the C-terminal capping AR. Mutations involving charged residues were found to have large effects on stability. Due to the difference in charge distribution in the internal ARs of E3_19 and E3_5, their interaction with the C-terminal capping AR is less favorable in E3_19. The simulation trajectories suggest that the stability of the designed AR proteins can be increased by optimizing the electrostatic interactions within and between the different repeats.
Publisher: Wiley
Date: 19-11-2019
Publisher: American Chemical Society (ACS)
Date: 25-07-2019
DOI: 10.26434/CHEMRXIV.8061845
Abstract: Targeted covalent inhibitor drugs require computational methods that go beyond simple molecular-mechanical force fields in order to model the chemical reactions that occur when they bind to their targets. Here, several semi-empirical and density-functional theory (DFT) methods are assessed for their ability to describe the potential energy surface and reaction energies of the covalent modification of a thiol by an electrophile. Functionals such as PBE and B3LYP fail to predict a stable enolate intermediate. This is largely due to delocalization error, which spuriously stabilizes the pre-reaction complex, in which excess electron density is transferred from the thiolate to the electrophile. Functionals with a high-exact exchange component, range-separated DFT functionals, and variationally-optimized exact exchange (i.e., the LC-B05minV functional) correct this issue to various degrees. The large gradient behaviour of the exchange enhancement factor is also found to significantly affect the results, leading to the improved performance of PBE0. While ωB97X-D and M06-2X were easonably accurate, no method provided quantitative accuracy for all three electrophiles, making this a very strenuous test of functional performance. Additionally, one drawback of M06-2X was that MD simulations using this functional were only stable if a fine integration grid was used. The low-cost semi-empirical methods, PM3, AM1, and PM7, provide a qualitatively correct description of the reaction mechanism, although the energetics are not quantitatively reliable. As a proof of concept, the potential of mean force for the addition of methylthiolate to MVK was calculated using QM/MM MD in an explicit polarizable aqueous solvent. br
Publisher: Proceedings of the National Academy of Sciences
Date: 16-12-2008
Abstract: The positions of protons are not available in most high-resolution structural data of biomolecules, thus the identity of proton storage sites in biomolecules that transport proton is generally difficult to determine unambiguously. Using combined quantum mechanical/molecular mechanical computations, we demonstrate that a pair of conserved glutamate residues (Glu 194/204) bonded by a delocalized proton is the proton release group that has been long sought in the proton pump, bacteriorhodopsin. This model is consistent with all available experimental structural and infrared data for both the wild-type bacteriorhodopsin and several mutants. In particular, the continuum infrared band in the 1,800- to 2,000-cm −1 region is shown to arise due to the partially delocalized nature of the proton between the glutamates in the wild-type bacteriorhodopsin alternations in the flexibility of the glutamates and electrostatic nature of nearby residues in various mutants modulate the degree of proton delocalization and therefore intensity of the continuum band. The strong hydrogen bond between Glu 194/204 also significantly shifts the carboxylate stretches of these residues well ,700 cm −1 , which explains why carboxylate spectral shift was not observed experimentally in the typical ,700-cm −1 region upon proton release. By contrast, simulations with the proton restrained on the nearby water cluster, as proposed by several recent studies [see, for ex le, Garezarek K, Gerwert K (2006) Functional waters in intraprotein proton transfer monitored by FTIR difference spectroscopy. Nature 439:109], led to significant structural deviations from available X-ray structures. This study establishes a biological function for strong, low-barrier hydrogen bonds.
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2022
DOI: 10.1101/2022.04.09.487726
Abstract: The bacteriophage λ red recombination system catalyzes the single-strand annealing homologous DNA recombination reaction, in which Redβ annealase protein plays a critical role. Using cryogenic electron microscopy, we were able to determine a structure of a C-terminally truncated Redβ with the residues 1-177 bound to two complementary 27mer oligonucleotides forming an annealing intermediate, to a final resolution of 3.3 Å. This structure validates and rationalizes decades of experimental observations on the biochemistry of Redβ. Definition of the interaction surfaces between subunits explains not only the DNA binding properties of Redβ, but also its propensity to oligomerize into long helical filaments, which are also formed by almost all annealases and are known to be functionally important. In addition, this annealing intermediate structure provides a detailed picture of the hydrogen bonding network that positions the DNA strands in a planar orientation to facilitate base pairing. Residues 133-138, which are missing from our structure, form a flexible loop. Molecular dynamics simulations were used to model the range of motion of the flexible loop, which suggested that it has a crucial role in keeping the DNA strands in the DNA-binding groove long enough to allow homology searching. The combination of structural and computational observations has allowed us to propose a detailed mechanism for the action of Redβ. More than half a century after its discovery, our work shines a light not only on the structure and mechanisms of Redβ, but also of other proteins within the annealase superfamilies. Single-strand annealing homologous DNA recombination is a process that is conserved throughout evolution from bacteriophages to humans, highlighting its importance and indispensability. It is a process that repairs double-stranded DNA breaks and is particularly vital in dsDNA viruses. The Redβ protein from the bacteriophage lambda is the archetypal annealase protein, forming the basis of our knowledge about this class of proteins. Along with the exonuclease λExo, these two proteins not only form the model system for single-strand annealing homologous recombination, but are also used in thousands of laboratories worldwide for performing genetic manipulations. After its discovery in 1966, we report the first structure of the DNA-binding and oligomerization domain of Redβ, providing details about the mechanism of homologous DNA annealing.
Publisher: American Chemical Society (ACS)
Date: 24-03-2021
Publisher: Springer Berlin Heidelberg
Date: 2013
DOI: 10.1007/128_2012_409
Publisher: American Chemical Society (ACS)
Date: 28-12-2018
Publisher: Springer Science and Business Media LLC
Date: 15-02-2019
DOI: 10.1038/S41598-018-38131-Z
Abstract: Streptococcus pneumoniae ( S . pneumoniae ) is a leading human pathogen, which takes large responsibility for severe otitis media, acute meningitis and septicaemia. It encodes up to three distinct sialidases: NanA, NanB and NanC, which are promising drug targets. Recent experimental studies have shown that these three sialidases might work together up to the ultimate step, where NanA and NanB produce N -acetylneuraminic acid (Neu5Ac) and 2,7-anhydro-Neu5Ac following the functions of sialidase and intramolecular trans -sialidase, whilst NanC carries on a ping-pong mechanism that produces or removes 2-deoxy-2,3-didehydro-Neu5AC. It is intriguing that these sialidases have similar active sites but operate via three distinct reaction pathways. To clarify this issue, herein we present the first systematic computational investigation on the catalytic pathways for S . pneumoniae NanA, NanB and NanC based on combined quantum mechanics/molecular mechanics simulations, and propose the most preferred routes for the three S . pneumoniae sialidases. Our findings support the mechanisms of NanA and NanC that were proposed by previous experimental studies, whereas the role of water in NanB was found to differ slightly from our current understandings. The mechanistic insights obtained from this work are expected to assist in the design of potent inhibitors targeting these key enzymes for therapeutic applications.
Publisher: Wiley
Date: 26-07-2022
DOI: 10.1111/CBDD.14115
Abstract: The Papain‐Like proteases (PLpro) of SARS‐CoV‐2 play a crucial role in viral replication and the formation of nonstructural proteins. To find available inhibitors, the 3D structure of PLpro of SARS2 was obtained by homologous modelling, and we used this structure as a target to search for inhibitors through molecular docking and MM/GBSA binding free energy rescoring. A novel hydrogen bonding penalty was applied to the screening process, which meanwhile took desolvation into account. Finally, 61 compounds were acquired and 4 of them with IC 50 at micromolar level tested in vitro enzyme activity assay, which includes clinical drugs tegaserod. Considering the importance of crystal water molecules, the 4 compounds were re‐docked and considered bound waters in the active site as a part of PLpro. The binding modes of these 4 compounds were further explored with metadynamics simulations. The hits will provide a starting point for future key interactions identified and lead optimization targetting PLpro.
Publisher: Wiley
Date: 20-04-2020
Publisher: American Chemical Society (ACS)
Date: 21-04-2022
DOI: 10.1021/JACS.1C13581
Abstract: BN/CC isosterism has been widely investigated as a strategy to expand carbon-based compounds. The introduction of BN units in organic molecules always results in novel properties. In this work, we reported the first synthesis and characterization of 1,6 ,3-bis-BN cyclohexane, an isostere of cyclohexane with two adjacent BN pairs. Its ring flipping barrier is similar to that of cyclohexane. Protic hydrogens on N in 1,6 ,3-bis-BN cyclohexane show higher reactivity than its isomeric bis-BN cyclohexane. This compound exhibits an appealing hydrogen storage capability of >9.0 wt %, nearly twice as much as the 1,2 ,5-bis-BN cyclohexane.
Publisher: American Chemical Society (ACS)
Date: 15-11-2021
DOI: 10.26434/CHEMRXIV-2021-N9HRB
Abstract: Density functional theory (DFT) is used in this work to predict the mechanism for constructing congested quaternary-quaternary carbon(sp3)–carbon(sp3) bonds in a pentanidium catalyzed substitution reaction. Computational mechanistic studies were carried out to investigate the proposed SN2X manifold, which consists of two primary elementary steps: halogen atom transfer (XAT) and subsequent SN2. For the first calculated model on original experimental substrates, XAT reaction barriers were more kinetically competitive than an SN2 pathway and connects to thermodynamically stable intermediates. Extensive computational screening-modelling were then done on various substrate combinations designed to study steric influence and to understand the mechanistic rationale, and calculations reveal that sterically congested substrates prefer the SN2X manifold over SN2. Different halides as leaving groups were also screened and it was found that the reactivity increases in order of Br Cl F in agreement of the strength of C–X bonds. However, DFT modelling suggests that chlorides can be a viable substrate for the SN2X process which should be further explored experimentally. Finally, ONIOM calculations on the full catalyst model were carried out to rationalize the stereoselectivity which corroborates with experimental results.
Publisher: American Chemical Society (ACS)
Date: 10-2007
DOI: 10.1021/JP074167R
Abstract: The standard self-consistent-charge density-functional-tight-binding (SCC-DFTB) method (Phys. Rev. B 1998, 58, 7260) is derived by a second-order expansion of the density functional theory total energy expression, followed by an approximation of the charge density fluctuations by charge monopoles and an effective d ed Coulomb interaction between the atomic net charges. The central assumptions behind this effective charge-charge interaction are the inverse relation of atomic size and chemical hardness and the use of a fixed chemical hardness parameter independent of the atomic charge state. While these approximations seem to be unproblematic for many covalently bound systems, they are quantitatively insufficient for hydrogen-bonding interactions and (anionic) molecules with localized net charges. Here, we present an extension of the SCC-DFTB method to incorporate third-order terms in the charge density fluctuations, leading to chemical hardness parameters that are dependent on the atomic charge state and a modification of the Coulomb scaling to improve the electrostatic treatment within the second-order terms. These modifications lead to a significant improvement in the description of hydrogen-bonding interactions and proton affinities of biologically relevant molecules.
Publisher: American Chemical Society (ACS)
Date: 06-11-2008
DOI: 10.1021/CT800330D
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C2FD20068F
Publisher: Springer Science and Business Media LLC
Date: 11-09-2011
DOI: 10.1038/NSMB.2113
Publisher: Informa UK Limited
Date: 12-2007
Publisher: American Chemical Society (ACS)
Date: 14-07-2010
DOI: 10.1021/JA103270W
Publisher: American Chemical Society (ACS)
Date: 04-10-2021
DOI: 10.26434/CHEMRXIV-2021-C6LRQ-V3
Abstract: The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising anti-metastasis target. 6-Substituted analogs of 5-N,N-(hexamethylene)amiloride (HMA) are potent and selective uPA inhibitors that lack the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. Here, computational and experimental findings reveal that residue 99 is a key contributor to the observed species selectivity, whereby enthalpically unfavorable expulsion of a water molecule by the 5-N,N-hexamethylene ring occurs when residue 99 is Tyr (as in mouse uPA). Analog 7 lacking the 5-N,N-hexamethylene ring maintained similar water networks when bound to human and mouse uPA and displayed reduced selectivity, thus supporting this conclusion. The study will guide further optimization of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.
Publisher: American Chemical Society (ACS)
Date: 10-08-2021
DOI: 10.26434/CHEMRXIV-2021-C6LRQ-V2
Abstract: The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising anti-metastasis target. 6-Substituted analogs of 5-N,N-(hexamethylene)amiloride (HMA) are potent and selective uPA inhibitors that lack the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. Here, computational and experimental findings reveal that residue 99 is a key contributor to the observed species selectivity, whereby enthalpically unfavorable expulsion of a water molecule by the 5-N,N-hexamethylene ring occurs when residue 99 is Tyr (as in mouse uPA). Analog 7 lacking the 5-N,N-hexamethylene ring maintained similar water networks when bound to human and mouse uPA and displayed reduced selectivity, thus supporting this conclusion. The study will guide further optimization of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.
Publisher: American Chemical Society (ACS)
Date: 19-07-2019
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9SC03215K
Abstract: The first reported catalytic reactivity of 5-allenyloxazolidinones is the tightly controlled, ergent synthesis of chiral 1,3-dienes or 5-vinyloxazolidinones under Pd(0) catalysis.
Publisher: American Chemical Society (ACS)
Date: 02-06-2009
DOI: 10.1021/JP901233V
Publisher: American Chemical Society (ACS)
Date: 29-01-2010
DOI: 10.1021/CT900576A
Publisher: American Chemical Society (ACS)
Date: 13-12-2021
DOI: 10.1021/ACS.JMEDCHEM.1C01423
Abstract: The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising antimetastasis target. 6-Substituted analogues of 5-
Publisher: American Chemical Society (ACS)
Date: 27-10-2022
Abstract: Solvents are one of the key variables in the optimization of a synthesis yield or properties of a synthesis product. In this paper, contemporary solvent models are applied to predict the rates of S
Publisher: American Chemical Society (ACS)
Date: 22-06-2021
DOI: 10.26434/CHEMRXIV-2021-C6LRQ
Abstract: Urokinase plasminogen activator (uPA) plays a critical role in tumour cell invasion and migration and is a promising anti-metastasis drug target. 6-Substituted analogues of 5-N,N-(hexamethylene)amiloride (HMA) are potent uPA inhibitors while lacking the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds as a class display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. We applied molecular dynamics simulations, free energy perturbation, X-ray crystallography and biochemical assays to understand the molecular basis of this selectivity. Our findings revealed that residue 99 is a key contributor to human/mouse selectivity, whereby enthalpically unfavourable steric expulsion of a water molecule by the 5-N,N-hexamethylene ring of HMA and analogues occurs when residue 99 is Tyr (as in mouse uPA). The study will serve to guide further optimisation of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-10-2010
Abstract: The Na/K pump is a P-type ATPase that exchanges three intracellular Na + ions for two extracellular K + ions through the plasmalemma of nearly all animal cells. The mechanisms involved in cation selection by the pump's ion-binding sites (site I and site II bind either Na + or K + site III binds only Na + ) are poorly understood. We studied cation selectivity by outward-facing sites (high K + affinity) of Na/K pumps expressed in Xenopus oocytes, under voltage cl . Guanidinium + , methylguanidinium + , and aminoguanidinium + produced two phenomena possibly reflecting actions at site III: ( i ) voltage-dependent inhibition (VDI) of outwardly directed pump current at saturating K + , and ( ii ) induction of pump-mediated, guanidinium-derivative–carried inward current at negative potentials without Na + and K + . In contrast, formamidinium + and acetamidinium + induced K + -like outward currents. Measurement of ouabain-sensitive ATPase activity and radiolabeled cation uptake confirmed that these cations are external K + congeners. Molecular dynamics simulations indicate that bound organic cations induce minor distortion of the binding sites. Among tested metals, only Li + induced Na + -like VDI, whereas all metals tested except Na + induced K + -like outward currents. Pump-mediated K + -like organic cation transport challenges the concept of rigid structural models in which ion specificity at site I and site II arises from a precise and unique arrangement of coordinating ligands. Furthermore, actions by guanidinium + derivatives suggest that Na + binds to site III in a hydrated form and that the inward current observed without external Na + and K + represents cation transport when normal occlusion at sites I and II is impaired. These results provide insights on external ion selectivity at the three binding sites.
Publisher: Elsevier BV
Date: 2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1MD00079A
Abstract: Key modifications of previous sialyltransferase inhibitors increased their activity against hST6Gal I and has further implications for synthetically accessible ST inhibitor design.
Publisher: Elsevier BV
Date: 11-2020
Publisher: American Chemical Society (ACS)
Date: 04-02-2006
DOI: 10.1021/JP056361O
Abstract: Motivated by the long-term goal of understanding vectorial biological processes such as proton transport (PT) in biomolecular ion pumps, a number of developments were made to establish combined quantum mechanical/molecular mechanical (QM/MM) methods suitable for studying chemical reactions involving significant charge separation in the condensed phase. These developments were summarized and discussed with representative problems. Specifically, free energy perturbation and boundary potential methods for treating long-range electrostatics were implemented to test the robustness of QM/MM results for protein systems. It was shown that consistent models with sufficient s ling were able to produce quantitatively satisfactory results, such as pKa for titritable groups in the interior of T4-lysozyme, while an inconsistent treatment of electrostatics or lack of sufficient s ling may produce incorrect results. Modifications were made to an approximate density functional theory (SCC-DFTB) to improve the description of proton affinity and hydrogen-bonding, which are crucial for the treatment of PT in polar systems. Test calculations on water autoionization showed clearly that both improvements are necessary for quantitatively reliable results. Finally, the newly established SCC-DFTB/MM-GSBP protocol was used to explore mechanistic issues in carbonic anhydrase (CA). Preliminary results suggest that PT in CA occurs mainly through short water wires containing two water molecules in a thermally activated fashion. Although longer water wires occur with similar frequencies, PT along those pathways, on average, has substantially higher barriers, a result not expected based on previous studies. The fluctuations of water molecules peripheral to the water wire were found to make a larger impact on the PT energetics compared to polar protein residues in the active site, which are largely pre-organized and therefore have less tendency to reorganize during the reaction.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2016
DOI: 10.1038/SREP20766
Abstract: Protein Tyrosine Phosphatase 1B (PTP1B) has been recognized as a promising therapeutic target for treating obesity, diabetes, and certain cancers for over a decade. Previous drug design has focused on inhibitors targeting the active site of PTP1B. However, this has not been successful because the active site is positively charged and conserved among the protein tyrosine phosphatases. Therefore, it is important to develop PTP1B inhibitors with alternative inhibitory strategies. Using computational studies including molecular docking, molecular dynamics simulations, and binding free energy calculations, we found that lupane triterpenes selectively inhibited PTP1B by targeting its more hydrophobic and less conserved allosteric site. These findings were verified using two enzymatic assays. Furthermore, the cell culture studies showed that lupeol and betulinic acid inhibited the PTP1B activity stimulated by TNFα in neurons. Our study indicates that lupane triterpenes are selective PTP1B allosteric inhibitors with significant potential for treating those diseases with elevated PTP1B activity.
Publisher: Public Library of Science (PLoS)
Date: 2007
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2QO00851C
Abstract: In this paper, a coupling partner-dependent unsymmetrical C–H functionalization of N -phenoxyacetamides leading to the formation of sophisticated spirocyclic scaffolds is presented.
Publisher: Public Library of Science (PLoS)
Date: 09-02-2007
Publisher: Cambridge University Press (CUP)
Date: 22-06-2021
DOI: 10.33774/CHEMRXIV-2021-C6LRQ
Abstract: Urokinase plasminogen activator (uPA) plays a critical role in tumour cell invasion and migration and is a promising anti-metastasis drug target. 6-Substituted analogues of 5-N,N-(hexamethylene)amiloride (HMA) are potent uPA inhibitors while lacking the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds as a class display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. We applied molecular dynamics simulations, free energy perturbation, X-ray crystallography and biochemical assays to understand the molecular basis of this selectivity. Our findings revealed that residue 99 is a key contributor to human/mouse selectivity, whereby enthalpically unfavourable steric expulsion of a water molecule by the 5-N,N-hexamethylene ring of HMA and analogues occurs when residue 99 is Tyr (as in mouse uPA). The study will serve to guide further optimisation of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.
Publisher: Wiley
Date: 16-12-2016
DOI: 10.1002/JMR.2520
Abstract: Human β-galactoside α-2,6-sialyltransferase I (hST6Gal I) catalyses the synthesis of sialylated glycoconjugates involved in cell-cell interactions. Overexpression of hST6Gal I is observed in many different types of cancers, where it promotes metastasis through altered cell surface sialylation. A wide range of sialyltransferase (ST) inhibitors have been developed based on the natural donor, cytidine 5'-monophosphate N-acetylneuraminic acid (CMP-Neu5Ac). Of these, analogues that are structurally similar to the transition state exhibit the highest inhibitory activity. In order to design inhibitors that are readily accessible synthetically and with favourable pharmacokinetic properties, an investigation of the replacement of the charged phosphodiester-linker, present in many ST inhibitors, with a potential neutral isostere such as a carbamate or a 1,2,3-triazole has been undertaken. To investigate this, molecular docking and molecular dynamics simulations were performed. These simulations provided an insight into the binding mode of previously reported phosphodiester-linked ST inhibitors and demonstrated that targeting the proposed sialyl acceptor site is a viable option for producing selective inhibitors. The potential for a carbamate- or triazole-linker as an isosteric replacement for the phosphodiester in transition-state analogue ST inhibitors was established using molecular docking. Molecular dynamics simulations of carbamate- and phosphodiester-linked compounds revealed that both classes exhibit consistent interactions with hST6Gal I. Overall, the results obtained from this study provide a rationale for synthetic and biological evaluation of triazole- and carbamate-linked transition-state analogue ST inhibitors as potential new antimetastatic agents.
Publisher: American Chemical Society (ACS)
Date: 13-09-2019
Abstract: Using density functional theory calculations, we explored the potential of defective MoS
Publisher: American Chemical Society (ACS)
Date: 03-08-2021
DOI: 10.26434/CHEMRXIV-2021-B5C49
Abstract: Here we report the vibrational spectra of deprotonated serine calculated from the classical molecular dynamics (MD) simulations and thermostated ring-polymer molecular dynamics (TRPMD) simulation with DFTB3. In our earlier study1 of deprotonated serine, we observed a significant difference in the vibrational spectra with the classical MD simulations compared to the infrared multiple photon dissociation (IRMPD) spectra. It was postulated that this is due to neglecting the nuclear quantum effects (NQEs). In this work, NQEs are considered in the spectral calculation using the TRPMD simulations. With the help of potential of mean force (PMF) calculations, the conformational space of deprotonated serine is analysed and used to understand the difference in the spectra of classical MD and TRPMD simulations at 298.15 K and 100 K. The high-frequency vibrational bands in the spectra are characterised using Fourier transform localised vibrational mode (FT-νNAC) and interatomic distance histograms. At room temperature, the quantum effects are less significant, and the free energy profiles in the classical MD and the TRPMD simulations are very similar. However, the hydrogen bond between the hydroxyl-carboxyl bond is slightly stronger in TRPMD simulations. At 100 K, the quantum effects are more prominent, especially in the 2600-3600 cm−1, and the free energy profile slightly differs between the classical MD and TRPMD simulations. Using the FT-νNAC and the interatomic distance histograms, the high-frequency vibrational bands are discussed in detail.
Publisher: Wiley
Date: 03-09-2003
DOI: 10.1002/PROT.10502
Abstract: We have performed molecular dynamics (MD) simulations to study the dimerization, folding, and binding to a protein of peptides containing an unnatural amino acid. NMR studies have shown that the substitution of one residue in a tripeptide beta-strand by the unnatural amino acid Hao (5-HO2CCONH-2-MeO-C6H3-CO-NHNH2) modifies the conformational flexibility of the beta-strand and the hydrogen-bonding properties of its two edges: The number of hydrogen-bond donors and acceptors increases at one edge, whereas at the other, they are sterically hindered. In simulations in chloroform, the Hao-containing peptide 9 (i-PrCO-Phe-Hao-Val-NHBu) forms a beta-sheet-like hydrogen-bonded dimer, in good agreement with the available experimental data. Addition of methanol to the solution induces instability of this beta-sheet, as confirmed by the experiments. MD simulations also reproduce the folding of the synthetic peptide 1a (i-PrCO-Hao-Ut-Phe-Ile-Leu-NHMe) into a beta-hairpin-like structure in chloroform. Finally, the Hao-containing peptide, Ac-Ala-Hao-Ala-NHMe, is shown to form a stable complex with the Ras analogue, Rap1 A, in water at room temperature. Together with the available experimental data, these simulation studies indicate that Hao-containing peptides may serve as inhibitors of beta-sheet interactions between proteins.
Publisher: Wiley
Date: 26-04-2016
Abstract: Ammonium aminodiboranate ([NH4 ][BH3 NH2 BH3 ]) is a long-sought isomer of diammoniate of diborane ([NH3 BH2 NH3 ][BH4 ]) and ammonia borane (NH3 BH3 ) dimer. Our results show that [NH4 ][BH3 NH2 BH3 ] is stable in tetrahydrofuran at -18 °C and decomposes rapidly to NH3 BH2 NH2 BH3 and H2 at elevated temperatures. The decomposition pathway is dictated by the dihydrogen bonding between H(δ+) on NH4 (+) and H(δ-) on BH3 , as confirmed by theoretical calculations. This is in contrast to the interconversion between [NH3 BH2 NH3 ][BH4 ] and (NH3 BH3 )2 , although all three have dihydrogen bonds and the same stoichiometry.
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3CC00475A
Abstract: The feasibility of various bespoke guanidine-based compounds as electrochemically regenerative biomimetic hydrides for reduction of carbon dioxide to formate were assessed by Density Functional Theory (DFT).
Publisher: Springer Science and Business Media LLC
Date: 2001
Abstract: A method of dynamically assembling molecular building blocks - DycoBlock - has been proposed and tested by Liu et al. This method is based on multiple-copy stochastic dynamics simulation in the presence of a receptor molecule. In this method, a novel algorithm was used to dynamically assemble the molecular building blocks to form candidate compounds. Currently, some new improvements have been incorporated into DycoBlock to make it more efficient. In the new version of DycoBlock, the binding energy and solvent accessible surface area (SASA) can be used to screen the resulting compounds. A simple clustering algorithm based on molecular similarity was developed and used to classify the remaining compounds. The revised DycoBlock was tested by breaking SC-558 - a selective inhibitor of cyclooxygenase-2 (COX-2) - into building blocks and reassembling them in the active site of the enzyme. The accuracy of recovery grew to 58.8% while it was only 16.7% in the previous version. Then, thirty-three kinds of molecular building blocks were used in the design of novel inhibitors and the investigation of ersity. As a result, a total of 1441 compounds was generated with high ersity. After the first screening procedure, there remained 864 reasonable compounds. The results from clustering indicate that the structural motifs in the diarylheterocycle class of COX-2-selective inhibitors have been generated using the revised DycoBlock, and their binding modes were investigated.
Publisher: Elsevier BV
Date: 10-2019
Publisher: American Chemical Society (ACS)
Date: 22-11-2006
DOI: 10.1021/JA065451J
Publisher: American Chemical Society (ACS)
Date: 04-03-2022
Abstract: Density functional theory (DFT) is used in this work to predict the mechanism for constructing congested quaternary-quaternary carbon(sp
Publisher: American Chemical Society (ACS)
Date: 30-08-2023
DOI: 10.26434/CHEMRXIV-2023-GR260
Abstract: The human Na+/H+ exchanger one (hNHE1) plays a crucial role in maintaining intracellular pH by regulating the electroneutral exchange of a single intracellular H+ for one extracellular Na+ across the plasma membrane. Understanding the molecular mechanisms governing ion transport and the binding of inhibitors is of importance in the development of anticancer therapeutics targeting hNHE1. In this context, we performed molecular dynamics (MD) simulations based on the recent cryo-electron microscopy (cryo-EM) structures of outward and inward-facing conformations of hNHE1. These simulations allowed us to explore the dynamics of the protein, examine the ion- translocation pore and confirm that Asp267 is the ion-binding residue. Our free energy calculations suggest that Na+ and K+ bind similarly at the ion-binding site. Consequently, Na+ over K+ selectivity cannot be solely explained by differences in ion binding. Our MD simulations involving hNHE1 inhibitors (cariporide and amiloride analogues), showed maintained stable interactions with Asp267 and Glu346. Our study highlights the importance of the salt bridge between the positively charged acylguanidine moiety and Asp267, which appears to play a role in the competitive inhibitory mechanism for this class of inhibitors. Our computational study provides a detailed mechanistic interpretation of experimental data and serves the basis of future structure-based inhibitor design.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7CP08364E
Abstract: Analysis of surface and chain length effects on the depolymerization of a phosphate-based lubricant at elevated temperature using first principles calculations.
Publisher: Rockefeller University Press
Date: 25-04-2011
Publisher: American Chemical Society (ACS)
Date: 16-08-2022
DOI: 10.26434/CHEMRXIV-2022-QZPV9
Abstract: Solvents are one of the key variables in the optimisation of a synthesis yield or properties of a synthesis product. In this paper, contemporary solvent models are applied to predict the rates of SN2 reactions in a range of aqueous and non-aqueous solvents. High-level CCSD(T)/CBS//M06-2X/6-31+G(d) gas phase energies were combined with solvation free energies from SMD, SM12 and ADF-COSMO-RS continuum solvent models as well as molecular mechanics (MM) explicit solvent models with different atomic charge schemes to predict the rate constants of three SN2 reactions in eight protic and aprotic solvents. It is revealed that popular solvent models struggle to predict their rate constants to within 3 log units of experimental values and deviations as large as 7.6 log units were observed. Amongst the implicit solvent models, the ADF-COSMO-RS model performed the best in predicting absolute rate constants with an average accuracy of 1.5 log units while the SM12 and CGenFF/TIP3P MM explicit solvent models were most accurate in the prediction of relative rate constants in different solvents due to systematic error cancellation. Free energy barriers obtained from umbrella s ling with explicit solvent QM/MM simulations led to excellent agreement with experiment provided that a validated level of theory is used to treat the QM region.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2014
Publisher: American Chemical Society (ACS)
Date: 02-04-2018
DOI: 10.1021/ACS.ANALCHEM.8B00469
Abstract: Separation and structural identification of lipids remain a major challenge for contemporary lipidomics. Regioisomeric lipids differing only in position(s) of unsaturation are often not differentiated by conventional liquid chromatography-mass spectrometry approaches leading to the incomplete, or sometimes incorrect, assignation of molecular structure. Here we describe an investigation of the gas phase separations by differential-mobility spectrometry (DMS) of a series of synthetic analogues of the recently described 1-deoxysphingosine. The dependence of the DMS behavior on the position of the carbon-carbon double bond within the ionized lipid is systematically explored and compared to trends from complementary investigations, including collision cross-sections measured by drift tube ion mobility, reaction efficiency with ozone, and molecular dynamics simulations. Consistent trends across these modes of interrogation point to the importance of direct, through-space interactions between the charge site and the carbon-carbon double bond. Differences in the geometry and energetics of this intramolecular interaction underpin DMS separations and influence reactivity trends between regioisomers. Importantly, the disruption and reformation of these intramolecular solvation interactions during DMS are proposed to be the causative factor in the observed separations of ionized lipids which are shown to have otherwise identical collision cross-sections. These findings provide key insights into the strengths and limitations of current ion-mobility technologies for lipid isomer separations and can thus guide a more systematic approach to improved analytical separations in lipidomics.
Publisher: American Chemical Society (ACS)
Date: 11-02-2020
Publisher: American Chemical Society (ACS)
Date: 21-06-2021
Publisher: AIP Publishing
Date: 16-12-2003
DOI: 10.1063/1.1523915
Abstract: The charge-on-spring method is used to develop a rigid, three-site, polarizable water model, a noniterative and a self-consistent version. In this method, the polarizability is taken into account by a variable separation of charges on selected polarizable centers. One of the pair of polarization charges resides on a polarizable center, while the other one is treated as an additional particle attached to the polarizable center by a parabolic restraint potential. The separation is calculated in response to the instantaneous electric field. We parametrized two models which are based on noniterative and self-consistent versions of the method, respectively. We computed several liquid-phase and gas-phase properties and compared with data available from experiment and ab initio calculations. The condensed-phase properties of both models are in reasonable accord with experiment, apart from discrepancies in electrostatic properties consistent with a slightly too large liquid-state dipole.
Publisher: American Chemical Society (ACS)
Date: 05-12-2019
Abstract: In this paper, density functional theory simulations were conducted to investigate the structural adaptation of sodium borates
Publisher: Springer Science and Business Media LLC
Date: 06-01-2022
Publisher: Elsevier BV
Date: 04-2020
Publisher: Wiley
Date: 11-09-2019
DOI: 10.1002/JCC.26064
Abstract: Targeted covalent inhibitor drugs require computational methods that go beyond simple molecular-mechanical force fields in order to model the chemical reactions that occur when they bind to their targets. Here, several semiempirical and density-functional theory (DFT) methods are assessed for their ability to describe the potential energy surface and reaction energies of the covalent modification of a thiol by an electrophile. Functionals such as PBE and B3LYP fail to predict a stable enolate intermediate. This is largely due to delocalization error, which spuriously stabilizes the prereaction complex, in which excess electron density is transferred from the thiolate to the electrophile. Functionals with a high-exact exchange component, range-separated DFT functionals, and variationally optimized exact exchange (i.e., the LC-B05minV functional) correct this issue to various degrees. The large gradient behavior of the exchange enhancement factor is also found to significantly affect the results, leading to the improved performance of PBE0. While ωB97X-D and M06-2X were reasonably accurate, no method provided quantitative accuracy for all three electrophiles, making this a very strenuous test of functional performance. Additionally, one drawback of M06-2X was that molecular dynamics (MD) simulations using this functional were only stable if a fine integration grid was used. The low-cost semiempirical methods, PM3, AM1, and PM7, provide a qualitatively correct description of the reaction mechanism, although the energetics is not quantitatively reliable. As a proof of concept, the potential of mean force for the addition of methylthiolate to methylvinyl ketone was calculated using quantum mechanical/molecular mechanical MD in an explicit polarizable aqueous solvent. © 2019 Wiley Periodicals, Inc.
Publisher: CSIRO Publishing
Date: 22-11-2021
DOI: 10.1071/CH21195
Abstract: Sialic acid occupies a privileged position at the terminus of the glycan chain of many cell-surface glycoconjugates. Owing to both their structure and location, charged sialic acid residues mediate numerous critical interactions in cell–cell communication including cell recognition, invasion, migration, receptor binding, and immunological responses. Sialyltransferases (STs) are the enzymes involved in the biosynthesis of sialylated glycans and are highly upregulated, up to 40–60 %, in a range of cancers, with tumour hypersialylation strongly correlated with both tumour progression and treatment resistance. Accordingly, inhibiting sialylation is currently being explored by several research groups worldwide as a potential new cancer treatment strategy. However, to progress small molecule ST inhibitors into the clinic, issues around selectivity, synthetic accessibility, and cell permeability need to be addressed. Using computationally guided design principles, we produced a leading series of ST inhibitors by replacing the cytidine nucleoside with uridine and substituting the charged phosphodiester linker with a carbamate or triazole moiety. Biological evaluation of the newly developed inhibitors was performed using commercially available human ST enzymes, with the Ki inhibition values of the lead compounds ranging from 1 to 20 µM. Compared with earlier generations of sialylation inhibitors, our inhibitors are non-toxic in a range of cell studies, with improved synthetic accessibility.
Publisher: American Chemical Society (ACS)
Date: 02-05-2019
DOI: 10.26434/CHEMRXIV.8061845.V1
Abstract: Targeted covalent inhibitor drugs require computational methods that go beyond simple molecular-mechanical force fields in order to model the chemical reactions that occur when they bind to their targets. Here, several semi-empirical and density-functional theory (DFT) methods are assessed for their ability to describe the potential energy surface and reaction energies of the covalent modification of a thiol by an electrophile. Functionals such as PBE and B3LYP fail to predict a stable enolate intermediate. This is largely due to delocalization error, which spuriously stabilizes the pre-reaction complex, in which excess electron density is transferred from the thiolate to the electrophile. Functionals with a high-exact exchange component, range-separated DFT functionals, and variationally-optimized exact exchange (i.e., the LC-B05minV functional) correct this issue to various degrees. The large gradient behaviour of the exchange enhancement factor is also found to significantly affect the results, leading to the improved performance of PBE0. While ωB97X-D and M06-2X were easonably accurate, no method provided quantitative accuracy for all three electrophiles, making this a very strenuous test of functional performance. Additionally, one drawback of M06-2X was that MD simulations using this functional were only stable if a fine integration grid was used. The low-cost semi-empirical methods, PM3, AM1, and PM7, provide a qualitatively correct description of the reaction mechanism, although the energetics are not quantitatively reliable. As a proof of concept, the potential of mean force for the addition of methylthiolate to MVK was calculated using QM/MM MD in an explicit polarizable aqueous solvent.
Publisher: American Chemical Society (ACS)
Date: 25-07-2019
DOI: 10.26434/CHEMRXIV.8061845.V2
Abstract: Targeted covalent inhibitor drugs require computational methods that go beyond simple molecular-mechanical force fields in order to model the chemical reactions that occur when they bind to their targets. Here, several semi-empirical and density-functional theory (DFT) methods are assessed for their ability to describe the potential energy surface and reaction energies of the covalent modification of a thiol by an electrophile. Functionals such as PBE and B3LYP fail to predict a stable enolate intermediate. This is largely due to delocalization error, which spuriously stabilizes the pre-reaction complex, in which excess electron density is transferred from the thiolate to the electrophile. Functionals with a high-exact exchange component, range-separated DFT functionals, and variationally-optimized exact exchange (i.e., the LC-B05minV functional) correct this issue to various degrees. The large gradient behaviour of the exchange enhancement factor is also found to significantly affect the results, leading to the improved performance of PBE0. While ωB97X-D and M06-2X were easonably accurate, no method provided quantitative accuracy for all three electrophiles, making this a very strenuous test of functional performance. Additionally, one drawback of M06-2X was that MD simulations using this functional were only stable if a fine integration grid was used. The low-cost semi-empirical methods, PM3, AM1, and PM7, provide a qualitatively correct description of the reaction mechanism, although the energetics are not quantitatively reliable. As a proof of concept, the potential of mean force for the addition of methylthiolate to MVK was calculated using QM/MM MD in an explicit polarizable aqueous solvent.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2017
DOI: 10.1038/S41598-017-14560-0
Abstract: Human β-galactoside α-2,6-sialyltransferase I (ST6Gal I) catalyses the synthesis of sialylated glycoconjugates. Overexpression of ST6Gal I is observed in many cancers, where it promotes metastasis through altered cell surface sialylation. A wide range of sialyltransferase inhibitors have been developed, with analogues structurally similar to the transition state exhibiting the highest inhibitory activity. To improve synthetic accessibility and pharmacokinetics of previously reported inhibitors, the replacement of the charged phosphodiester linker with a potential neutral isostere such as a carbamate or a 1,2,3-triazole has been investigated. Extensive molecular dynamics simulations have demonstrated that compounds with the alternate linkers could maintain key interactions with the human ST6Gal I active site, demonstrating the potential of a carbamate or a 1,2,3-triazole as a phosphodiester isostere. Free energy perturbation calculations provided energetic evidence suggesting that the carbamate and 1,2,3-triazole were slightly more favourable than the phosphodiester. Further exploration with free energy component, quasi-harmonic and cluster analysis suggested that there is an enthalpy-entropy compensation accounting for the replacement of the flexible charged phosphodiester with a neutral and rigid isostere. Overall, these simulations provide a strong rationale for the use of a carbamate or 1,2,3-triazole as a phosphodiester isostere in the development of novel inhibitors of human ST6Gal I.
Publisher: Public Library of Science (PLoS)
Date: 27-11-2018
Publisher: Elsevier BV
Date: 11-2005
Publisher: Wiley
Date: 14-05-2004
Abstract: In order to study the differences of the structural properties of Aib-rich peptides in solution and in the crystalline state, molecular dynamics (MD) simulations of the Aib-containing peptide II (pBrBz-(Aib)5-Leu-(Aib)2-OMe) were performed in the crystalline state, starting from two different conformers obtained experimentally by X-ray diffraction. The structural properties as derived from X-ray crystallography (e.g., torsional angles and hydrogen bonds) are well-reproduced in both constant-volume and constant-pressure simulations, although the force-field parameters used result in a too-high density of the crystals. Through comparison with the results from previous MD and nuclear magnetic resonance (NMR) studies of the very similar peptide I (Z-(Aib)s-Leu-(Aib)2-OMe) in dimethylsulfoxide (DMSO) solution, it is found that, in the crystal simulation, the conformational distribution of peptide II is much narrower than that in the solution simulation of peptide. I. This leads to a significant difference in 3 [symbol: see text] (HN, HC alpha) coupling constant values, in agreement with experimental data, whereas the NOE intensities or proton-proton distance bounds appear insensitive to the difference in conformational distribution. For small peptides the differences between their conformational distribution in the crystalline form and in solution may be much larger than for proteins, a fact which should be kept in mind when interpreting molecular properties in the solution state by using X-ray crystallographic data.
Publisher: Elsevier BV
Date: 2017
Start Date: 2021
End Date: 2023
Funder: Australian Research Data Commons
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End Date: 2019
Funder: Australian Research Council
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Funder: Australian Research Council
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Funder: Australian Research Council
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Funder: National Health and Medical Research Council
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End Date: 2024
Funder: Australian Research Council
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End Date: 03-2025
Amount: $460,000.00
Funder: Australian Research Council
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End Date: 12-2020
Amount: $391,000.00
Funder: Australian Research Council
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End Date: 12-2017
Amount: $584,493.00
Funder: Australian Research Council
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End Date: 12-2016
Amount: $1,025,000.00
Funder: Australian Research Council
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