pH-Replica Exchange Molecular Dynamics in Proteins Using a Discrete Protonation Method

Dashti, Danial Sabri; Meng, Yiming; Roitberg, Adrián E.

doi:10.1021/jp303385x

Cited by 44 publications

(38 citation statements)

References 61 publications

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“…This scenario, although contrived, is a strong argument in favor of using a wide range of pH values (an extent of at least four units seems reasonable) or even using an expanded ensemble in which the pH is able to vary. 11,22,58 A complementary and/or alternative adjustment consists in selectively deactivating the inherent p K a algorithm for a small subset of residues that are either suspected of being important or have otherwise uncharacterized behavior. This can be done by trivially setting the inherent p K a equal to the pH.…”

Section: Resultsmentioning

confidence: 99%

Constant-pH Molecular Dynamics Simulations for Large Biomolecular Systems

Radak

Chipot

Suh

et al. 2017

J. Chem. Theory Comput.

166

218

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An increasingly important endeavor is to develop computational strategies that enable molecular dynamics (MD) simulations of biomolecular systems with spontaneous changes in protonation states under conditions of constant pH. The present work describes our efforts to implement the powerful constant-pH MD simulation method based on a hybrid nonequilibrium MD/Monte Carlo (neMD/MC) technique within the highly scalable program NAMD. The constant-pH hybrid neMD/MC method has a number of appealing features; it samples the correct semi-grand canonical ensemble rigorously, the computational cost increases linearly with the number of titratable sites, and it is applicable to explicit solvent simulations. The present implementation of the constant-pH hybrid neMD/MC in NAMD is designed to handle a wide range of biomolecular systems with no constraints on the choice of force field. Furthermore, the sampling efficiency can be adaptively improved on-the-fly by adjusting algorithmic parameters during the simulation. Illustrative examples emphasizing medium and large scale applications on next-generation supercomputing architectures are provided.

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Section: Resultsmentioning

confidence: 99%

Constant-pH Molecular Dynamics Simulations for Large Biomolecular Systems

Radak

Chipot

Suh

et al. 2017

J. Chem. Theory Comput.

166

218

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“…Based on the data of 11 residues from the engineered mutants as well as the wild-type variant of SNase, McCammon and coworkers concluded that while the accuracy of the DpHMD method for predicting the p K a ’s of surface sidechains is high (root-mean-square error of 1.2 units), challenge remains for interior and coupled sites which require increased sampling and accelerated convergence [37]. To address this issue, the Roitberg group and others applied the pH-REX protocol to revisit the p K a calculation of hen egg white lysozyme (HEWL) [19] and small peptides [38, 39]. For more detailed discussion of the blind prediction results we direct the reader to the review article by Alexov et al [36].…”

Section: Recent Applications Of Constant Ph Molecular Dynamicsmentioning

confidence: 99%

Recent development and application of constant pH molecular dynamics

Chen

Shi

Shen

2014

Molecular Simulation

114

128

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Solution pH is a critical environmental factor for chemical and biological processes. Over the last decade, significant efforts have been made in the development of constant pH molecular dynamics (pHMD) techniques for gaining detailed insights into pH-coupled dynamical phenomena. In this article we review the advancement of this field in the past five years, placing a special emphasis on the development of the all-atom continuous pHMD technique. We discuss various applications, including the prediction of pKa shifts for proteins, nucleic acids and surfactant assemblies, elucidation of pH-dependent population shifts, protein-protein and protein-RNA binding, as well as the mechanisms of pH-dependent self-assembly and phase transitions of surfactants and peptides. We also discuss future directions for the further improvement of the pHMD techniques.

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“…The structure of the E2 monomer has not been reported previously; thus, the isolated E2 was adapted from the FI state with some equilibration through molecular dynamics to serve as a reference accounting for the possible metastable postdissociation state. The pH replica exchange MD (molecular dynamics) simulations were carried out to determine the pK a values of Asp, Glu, and His residues (54)(55)(56)(57). During the pH replica exchange MD simulations, the alchemical variable-λ is propagated according to the extended Hamiltonian equations of motions (54,55), characterizing varying protonation from fully deprotonated (λ = 1) to protonated (λ = 0) residues.…”

Section: Theory and Methodsmentioning

confidence: 99%

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

Zhang

Mukhopadhyay

Brooks

2015

Proc. Natl. Acad. Sci. U.S.A.

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Alphavirus envelope proteins, organized as trimers of E2-E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections. 3). The lack of a vaccine or specific treatment prompts investigations of the fundamental mechanisms of the alphaviral lifecycle to facilitate the development of effective antiviral therapies (4). Alphaviruses have been reported to enter the cell through receptor-mediated endocytosis. Here, alphaviruses are ferried toward the perinuclear space of the host cell inside vesicles towed by molecular motors and delivered to specific locations for productive replication (5-11). Even when direct entry into the cytoplasm is possible (11-15), the endocytic entry pathway facilitates the transportation of viruses across the crowded cytoplasmic space and delays detection by the immune system without leaving empty capsid or envelope as obvious evidence of the viral infection exposed outside the host cell (10, 11). Before the delivery of its viral genome into the cytoplasm of a host cell, the alphavirus must undergo a critical step of low pH-triggered membrane fusion, which is a common mechanism in the endocytic viral entry pathway among many different viruses. Understanding the mechanism of the low pH-triggered alphaviral membrane fusion is essential for the development of therapies against alphavirus as well as other viruses using similar endocytic entry mechanisms.Recent studies of the lifecycle of alphavirus reveal that a precursor, p62, is first synthesized as a chaperon forming a heterodimer with E1, which is essential for viral budding (16); p62 protects the E1 protein in the low-pH environment of the secretory pathway before being cleaved by cellular furin to produce mature E2-E1 and a smaller fragment, E3 (17-21). After the virus buds from the cytoplasmic membrane, E3 is released from the virus particle under neutral pH conditions outside the host cell (13,(22)(23)(24).On the surface of a mature alphavirus, 80 (E2-E1) 3 viral spikes, organized in T = 4 icosahedral symmetry on the viral lipid membrane, enclose the viral capsid and genome (25-43). On internalization of the mature virus in the endosome of the host cell in a new round of infection cycle, the ...

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pH-Replica Exchange Molecular Dynamics in Proteins Using a Discrete Protonation Method

Cited by 44 publications

References 61 publications

Constant-pH Molecular Dynamics Simulations for Large Biomolecular Systems

Constant-pH Molecular Dynamics Simulations for Large Biomolecular Systems

Recent development and application of constant pH molecular dynamics

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

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