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Li M.,East China Normal University | Zhang J.Z.H.,East China Normal University | Zhang J.Z.H.,Center for Computational Chemistry at Shanghai | Zhang J.Z.H.,New York University
Physical Chemistry Chemical Physics | Year: 2017

The development of polarizable water models at coarse-grained (CG) levels is of much importance to CG molecular dynamics simulations of large biomolecular systems. In this work, we combined the newly developed two-bead multipole force field (TMFF) for proteins with the two-bead polarizable water models to carry out CG molecular dynamics simulations for benchmark proteins. In our simulations, two different two-bead polarizable water models are employed, the RTPW model representing five water molecules by Riniker et al. and the LTPW model representing four water molecules. The LTPW model is developed in this study based on the Martini three-bead polarizable water model. Our simulation results showed that the combination of TMFF with the LTPW model significantly stabilizes the protein's native structure in CG simulations, while the use of the RTPW model gives better agreement with all-atom simulations in predicting the residue-level fluctuation dynamics. Overall, the TMFF coupled with the two-bead polarizable water models enables one to perform an efficient and reliable CG dynamics study of the structural and functional properties of large biomolecules. © the Owner Societies 2017.

Marsalek O.,New York University | Chen P.-Y.,New York University | Dupuis R.,University Paul Sabatier | Benoit M.,CNRS Toulouse Center for Materials Elaboration and Structural Studies | And 6 more authors.
Journal of Chemical Theory and Computation | Year: 2014

The problem of computing free energy differences due to isotopic substitution in chemical systems is discussed. The shift in the equilibrium properties of a system upon isotopic substitution is a purely quantum mechanical effect that can be quantified using the Feynman path integral approach. In this paper, we explore two developments that lead to a highly efficient path integral scheme. First, we employ a mass switching function inspired by the work of Ceriotti and Markland [ J. Chem. Phys. 2013, 138, 014112] that is based on the inverse square root of the mass and which leads to a perfectly constant free energy derivative with respect to the switching parameter in the harmonic limit. We show that even for anharmonic systems, this scheme allows a single-point thermodynamic integration approach to be used in the construction of free energy differences. In order to improve the efficiency of the calculations even further, however, we derive a set of free energy derivative estimators based on the fourth-order scheme of Takahashi and Imada [ J. Phys. Soc. Jpn. 1984, 53, 3765]. The Takahashi-Imada procedure generates a primitive fourth-order estimator that allows the number of imaginary time slices in the path-integral approach to be reduced substantially. However, as with all primitive estimators, its convergence is plagued by numerical noise. In order to alleviate this problem, we derive a fourth-order virial estimator based on a transferring of the difference between second- and fourth-order primitive estimators, which remains relatively constant as a function of the number of configuration samples, to the second-order virial estimator. We show that this new estimator converges as smoothly as the second-order virial estimator but requires significantly fewer imaginary time points. © 2014 American Chemical Society.

Zhou J.,Sun Yat Sen University | Li M.,Sun Yat Sen University | Chen N.,Sun Yat Sen University | Wang S.,New York University | And 4 more authors.
ACS Chemical Biology | Year: 2015

Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2-selective inhibitor, β-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the β-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2. © 2014 American Chemical Society.

Margul D.T.,New York University | Tuckerman M.E.,New York University | Tuckerman M.E.,Courant Institute of Mathematical Sciences | Tuckerman M.E.,Center for Computational Chemistry at Shanghai
Journal of Chemical Theory and Computation | Year: 2016

Molecular dynamics remains one of the most widely used computational tools in the theoretical molecular sciences to sample an equilibrium ensemble distribution and/or to study the dynamical properties of a system. The efficiency of a molecular dynamics calculation is limited by the size of the time step that can be employed, which is dictated by the highest frequencies in the system. However, many properties of interest are connected to low-frequency, long time-scale phenomena, requiring many small time steps to capture. This ubiquitous problem can be ameliorated by employing multiple time-step algorithms, which assign different time steps to forces acting on different time scales. In such a scheme, fast forces are evaluated more frequently than slow forces, and as the former are often computationally much cheaper to evaluate, the savings can be significant. Standard multiple time-step approaches are limited, however, by resonance phenomena, wherein motion on the fastest time scales limits the step sizes that can be chosen for the slower time scales. In atomistic models of biomolecular systems, for example, the largest time step is typically limited to around 5 fs. Previously, we introduced an isokinetic extended phase-space algorithm (Minary et al. Phys. Rev. Lett. 2004, 93, 150201) and its stochastic analog (Leimkuhler et al. Mol. Phys. 2013, 111, 3579) that eliminate resonance phenomena through a set of kinetic energy constraints. In simulations of a fixed-charge flexible model of liquid water, for example, the time step that could be assigned to the slow forces approached 100 fs. In this paper, we develop a stochastic isokinetic algorithm for multiple time-step molecular dynamics calculations using a polarizable model based on fluctuating dipoles. The scheme developed here employs two sets of induced dipole moments, specifically, those associated with short-range interactions and those associated with a full set of interactions. The scheme is demonstrated on the polarizable AMOEBA water model. As was seen with fixed-charge models, we are able to obtain large time steps exceeding 100 fs, allowing calculations to be performed 10 to 20 times faster than standard thermostated molecular dynamics. © 2016 American Chemical Society.

Xiao X.,East China Normal University | Zhu T.,East China Normal University | Ji C.G.,East China Normal University | Ji C.G.,Center for Computational Chemistry at Shanghai | And 2 more authors.
Journal of Physical Chemistry B | Year: 2013

An effective polarizable bond (EPB) model has been developed for computer simulation of proteins. In this partial polarizable approach, all polar groups of amino acids are treated as polarizable, and the relevant polarizable parameters were determined by fitting to quantum calculated electrostatic properties of these polar groups. Extensive numerical tests on a diverse set of proteins (including 1IEP, 1MWE, 1NLJ, 4COX, 1PGB, 1K4C, 1MHN, 1UBQ, 1IGD) showed that this EPB model is robust in MD simulation and can correctly describe the structure and dynamics of proteins (both soluble and membrane proteins). Comparison of the computed hydrogen bond properties and dynamics of proteins with experimental data and with results obtained from the nonpolarizable force field clearly demonstrated that EPB can produce results in much better agreement with experiment. The averaged deviation of the simulated backbone N-H order parameter of the B3 immunoglobobulin-binding domain of streptococcal protein G from experimental observation is 0.0811 and 0.0332 for Amber99SB and EPB, respectively. This new model inherited the effective character of the classic force field and the fluctuating feature of previous polarizable models. Different from other polarizable models, the polarization cost energy is implicitly included in the present method. As a result, the present method avoids the problem of over polarization and is numerically stable and efficient for dynamics simulation. Finally, compared to the traditional fixed AMBER charge model, the present method only adds about 5% additional computational time and is therefore highly efficient for practical applications. © 2013 American Chemical Society.

Ozer G.,New York University | Collepardo-Guevara R.,University of Cambridge | Schlick T.,New York University | Schlick T.,Courant Institute of Mathematical Sciences | Schlick T.,Center for Computational Chemistry at Shanghai
Journal of Physics Condensed Matter | Year: 2015

The chromatin fiber undergoes significant structural changes during the cell's life cycle to modulate DNA accessibility. Detailed mechanisms of such structural transformations of chromatin fibers as affected by various internal and external conditions such as the ionic conditions of the medium, the linker DNA length, and the presence of linker histones, constitute an open challenge. Here we utilize Monte Carlo (MC) simulations of a coarse grained model of chromatin with nonuniform linker DNA lengths as found in vivo to help explain some aspects of this challenge. We investigate the unfolding mechanisms of chromatin fibers with alternating linker lengths of 26-62bp and 44-79bp using a series of end-to-end stretching trajectories with and without linker histones and compare results to uniform-linker-length fibers. We find that linker histones increase overall resistance of nonuniform fibers and lead to fiber unfolding with superbeads-on-a-string cluster transitions. Chromatin fibers with nonuniform linker DNA lengths display a more complex, multi-step yet smoother process of unfolding compared to their uniform counterparts, likely due to the existence of a more continuous range of nucleosome-nucleosome interactions. This finding echoes the theme that some heterogeneity in fiber component is biologically advantageous. © 2015 IOP Publishing Ltd.

Chen J.,Shandong Jiaotong University | Wang X.,Center for Computational Chemistry at Shanghai | Zhu T.,East China Normal University | Zhang Q.,Shandong Normal University | And 2 more authors.
Journal of Chemical Information and Modeling | Year: 2015

Drug resistance of mutations V32I, G48V, I50V, I54V, and I84V in HIV-1 protease (PR) was found in clinical treatment of HIV patients with the drug amprenavir (APV). In order to elucidate the molecular mechanism of drug resistance associated with these mutations, the thermodynamic integration (TI) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods were applied to calculate binding free energies of APV to wild-type PR and these mutated PRs. The relative binding free energy differences from the TI calculations reveal that the decrease in van der Waals interactions of APV with mutated PRs relative to the wild-type PR mainly drives the drug resistance. This result is in good agreement with the previous experimental results and is also consistent with the results from MM-PBSA calculations. Analyses based on molecular dynamics trajectories show that these mutations can adjust the shape and conformation of the binding pocket, which provides main contributions to the decrease in the van der Waals interactions of APV with mutated PRs. The present study could provide important guidance for the design of new potent inhibitors that could alleviate drug resistance of PR due to mutations. © 2015 American Chemical Society.

Schneider E.,New York University | Vogt L.,New York University | Tuckerman M.E.,New York University | Tuckerman M.E.,Courant Institute of Mathematical Sciences | Tuckerman M.E.,Center for Computational Chemistry at Shanghai
Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials | Year: 2016

Prediction and exploration of possible polymorphism in organic crystal compounds are of great importance for industries ranging from organic electronics to pharmaceuticals to high-energy materials. Here we apply our crystal structure prediction procedure and the enhanced molecular dynamics based sampling approach called the Crystal-Adiabatic Free Energy Dynamics (Crystal-AFED) method to benzene and naphthalene. Crystal-AFED allows the free energy landscape of structures to be explored efficiently at any desired temperature and pressure. For each system, we successfully predict the most stable crystal structures at atmospheric pressure and explore the relative Gibbs free energies of predicted polymorphs at high pressures. Using Crystal-AFED sampling, we find that mixed structures, which typically cannot be discovered by standard crystal structure prediction methods, are prevalent in the solid forms of these compounds at high pressure.The crystal structures of benzene and naphthalene are successfully predicted for atmospheric and high-pressure conditions. Using enhanced molecular dynamics based sampling, we find that mixed structures, which typically cannot be discovered by standard crystal structure prediction methods, are prevalent in the solid forms of these compounds at high pressure. © International Union of Crystallography, 2016.

Xu M.,New York University | Jimenez-Ruiz M.,Laue Langevin Institute | Johnson M.R.,Laue Langevin Institute | Rols S.,Laue Langevin Institute | And 7 more authors.
Physical Review Letters | Year: 2014

We report an inelastic neutron scattering (INS) study of a H2 molecule encapsulated inside the fullerene C60 which confirms the recently predicted selection rule, the first to be established for the INS spectroscopy of aperiodic, discrete molecular compounds. Several transitions from the ground state of para-H2 to certain excited translation-rotation states, forbidden according to the selection rule, are systematically absent from the INS spectra, thus validating the selection rule with a high degree of confidence. Its confirmation sets a precedent, as it runs counter to the widely held view that the INS spectroscopy of molecular compounds is not subject to any selection rules. © 2014 American Physical Society.

Lei J.,Nanjing University | Zhou Y.,Nanjing University | Xie D.,Nanjing University | Xie D.,Anhui University of Science and Technology | And 2 more authors.
Journal of the American Chemical Society | Year: 2015

Aspirin, one of the oldest and most common anti-inflammatory agents, has recently been shown to reduce cancer risks. The principal pharmacological effects of aspirin are known to arise from its covalent modification of cyclooxygenase-2 (COX-2) through acetylation of Ser530, but the detailed mechanism of its biochemical action and specificity remains to be elucidated. In this work, we have filled this gap by employing a state-of-the-art computational approach, Born-Oppenheimer molecular dynamics simulations with ab initio quantum mechanical/molecular mechanical potential and umbrella sampling. Our studies have characterized a substrate-assisted inhibition mechanism for aspirin acetylating COX: it proceeds in two successive stages with a metastable tetrahedral intermediate, in which the carboxyl group of aspirin serves as the general base. The computational results confirmed that aspirin would be 10-100 times more potent against COX-1 than against COX-2, and revealed that this inhibition specificity between the two COX isoforms can be attributed mainly to the difference in kinetics rate of the covalent inhibition reaction, not the aspirin-binding step. The structural origin of this differential inhibition of the COX enzymes by aspirin has also been elucidated. © 2014 American Chemical Society.

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