Dataset Information

Titr-DMD-A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework.

ABSTRACT: The pH-dependence of enzyme fold stability and catalytic activity is a fundamentally dynamic, structural property which is difficult to study. The challenges and expense of investigating dynamic, atomic scale behavior experimentally means that computational methods, particularly constant pH molecular dynamics (CpHMD), are well situated tools for this. However, these methods often struggle with affordable sampling of sufficiently long time scales while also obtaining accurate pK_a prediction and verifying the structures they generate. We introduce Titr-DMD, an affordable CpHMD method that combines the quasi-all-atom coarse-grained discrete molecular dynamics (DMD) method for conformational sampling with Propka for pK_a prediction, to circumvent these issues. The combination enables rapid sampling on limited computational resources, while simulations are still performed on the atomic scale. We benchmark the method on a set of proteins with experimentally attested pK_a and on the pH triggered conformational change in a staphylococcal nuclease mutant, a rare experimental study of such behavior. Our results show Titr-DMD to be an effective and inexpensive method to study pH-coupled protein dynamics.

SUBMITTER: Reilley DJ

PROVIDER: S-EPMC10662685 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Titr-DMD-A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework.

Reilley David J DJ Wang Jian J Dokholyan Nikolay V NV Alexandrova Anastassia N AN

Journal of chemical theory and computation 20210624 7

The pH-dependence of enzyme fold stability and catalytic activity is a fundamentally dynamic, structural property which is difficult to study. The challenges and expense of investigating dynamic, atomic scale behavior experimentally means that computational methods, particularly constant pH molecular dynamics (CpHMD), are well situated tools for this. However, these methods often struggle with affordable sampling of sufficiently long time scales while also obtaining accurate p<i>K</i><sub>a</sub ...[more]

PMID: 34165292

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Project description:Constant pH molecular dynamics (MD) simulations sample protonation states on the fly according to the conformational environment and user specified pH conditions; however, the current accuracy is limited due to the use of implicit-solvent models or a hybrid solvent scheme. Here, we report the first GPU-accelerated implementation, parametrization, and validation of the all-atom continuous constant pH MD (CpHMD) method with particle-mesh Ewald (PME) electrostatics in the Amber22 pmemd.cuda engine. The titration parameters for Asp, Glu, His, Cys, and Lys were derived for the CHARMM c22 and Amber ff14sb and ff19sb force fields. We then evaluated the PME-CpHMD method using the asynchronous pH replica-exchange titration simulations with the c22 force field for six benchmark proteins, including BBL, hen egg white lysozyme (HEWL), staphylococcal nuclease (SNase), thioredoxin, ribonuclease A (RNaseA), and human muscle creatine kinase (HMCK). The root-mean-square deviation from the experimental pKa's of Asp, Glu, His, and Cys is 0.76 pH units, and the Pearson's correlation coefficient for the pKa shifts with respect to model values is 0.80. We demonstrated that a finite-size correction or much enlarged simulation box size can remove a systematic error of the calculated pKa's and improve agreement with experiment. Importantly, the simulations captured the relevant biology in several challenging cases, e.g., the titration order of the catalytic dyad Glu35/Asp52 in HEWL and the coupled residues Asp19/Asp21 in SNase, the large pKa upshift of the deeply buried catalytic Asp26 in thioredoxin, and the large pKa downshift of the deeply buried catalytic Cys283 in HMCK. We anticipate that PME-CpHMD will offer proper pH control to improve the accuracies of MD simulations and enable mechanistic studies of proton-coupled dynamical processes that are ubiquitous in biology but remain poorly understood due to the lack of experimental tools and limitation of current MD simulations.

Dataset Information

Titr-DMD-A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework.

Publications

Titr-DMD-A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework.

Similar Datasets

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