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Generalized Born Based Continuous Constant pH Molecular Dynamics in Amber: Implementation, Benchmarking and Analysis.

ABSTRACT: Solution pH plays an important role in structure and dynamics of biomolecular systems; however, pH effects cannot be accurately accounted for in conventional molecular dynamics simulations based on fixed protonation states. Continuous constant pH molecular dynamics (CpHMD) based on the ?-dynamics framework calculates protonation states on the fly during dynamical simulation at a specified pH condition. Here we report the CPU-based implementation of the CpHMD method based on the GBNeck2 generalized Born (GB) implicit-solvent model in the pmemd engine of the Amber molecular dynamics package. The performance of the method was tested using pH replica-exchange titration simulations of Asp, Glu and His side chains in 4 miniproteins and 7 enzymes with experimentally known p Ka's, some of which are significantly shifted from the model values. The added computational cost due to CpHMD titration ranges from 11 to 33% for the data set and scales roughly linearly as the ratio between the titrable sites and number of solute atoms. Comparison of the experimental and calculated p Ka's using 2 ns per replica sampling yielded a mean unsigned error of 0.70, a root-mean-squared error of 0.91, and a linear correlation coefficient of 0.79. Though this level of accuracy is similar to the GBSW-based CpHMD in CHARMM, in contrast to the latter, the current implementation was able to reproduce the experimental orders of the p Ka's of the coupled carboxylic dyads. We quantified the sampling errors, which revealed that prolonged simulation is needed to converge p Ka's of several titratable groups involved in salt-bridge-like interactions or deeply buried in the protein interior. Our benchmark data demonstrate that GBNeck2-CpHMD is an attractive tool for protein p Ka predictions.

SUBMITTER: Huang Y

PROVIDER: S-EPMC6516748 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Generalized Born Based Continuous Constant pH Molecular Dynamics in Amber: Implementation, Benchmarking and Analysis.

Huang Yandong Y Harris Robert C RC Shen Jana J

Journal of chemical information and modeling 20180711 7

Solution pH plays an important role in structure and dynamics of biomolecular systems; however, pH effects cannot be accurately accounted for in conventional molecular dynamics simulations based on fixed protonation states. Continuous constant pH molecular dynamics (CpHMD) based on the λ-dynamics framework calculates protonation states on the fly during dynamical simulation at a specified pH condition. Here we report the CPU-based implementation of the CpHMD method based on the GBNeck2 generaliz ...[more]

PMID: 29949356

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Project description:We present a GPU implementation of the continuous constant pH molecular dynamics (CpHMD) based on the most recent generalized Born implicit-solvent model in the pmemd engine of the Amber molecular dynamics package. To test the accuracy of the tool for rapid pKa predictions, a series of 2 ns single-pH simulations were performed for over 120 titratable residues in 10 benchmark proteins that were previously used to test the various continuous CpHMD methods. The calculated pKa's showed a root-mean-square deviation of 0.80 and correlation coefficient of 0.83 with respect to experiment. Also, 90% of the pKa's were converged with estimated errors below 0.1 pH units. Surprisingly, this level of accuracy is similar to our previous replica-exchange simulations with 2 ns per replica and an exchange attempt frequency of 2 ps-1 (Huang, Harris, and Shen J. Chem. Inf. Model. 2018 , 58 , 1372 - 1383 ). Interestingly, for the linked titration sites in two enzymes, although residue-specific protonation state sampling in the single-pH simulations was not converged within 2 ns, the protonation fraction of the linked residues appeared to be largely converged, and the experimental macroscopic pKa values were reproduced to within 1 pH unit. Comparison with replica-exchange simulations with different exchange attempt frequencies showed that the splitting between the two macroscopic pKa's is underestimated with frequent exchange attempts such as 2 ps-1, while single-pH simulations overestimate the splitting. The same trend is seen for the single-pH vs replica-exchange simulations of a hydrogen-bonded aspartyl dyad in a much larger protein. A 2 ns single-pH simulation of a 400-residue protein takes about 1 h on a single NVIDIA GeForce RTX 2080 graphics card, which is over 1000 times faster than a CpHMD run on a single CPU core of a high-performance computing cluster node. Thus, we envision that GPU-accelerated continuous CpHMD may be used in routine pKa predictions for a variety of applications, from assisting MD simulations with protonation state assignment to offering pH-dependent corrections of binding free energies and identifying reactive hot spots for covalent drug design.

Dataset Information

Generalized Born Based Continuous Constant pH Molecular Dynamics in Amber: Implementation, Benchmarking and Analysis.

Publications

Generalized Born Based Continuous Constant pH Molecular Dynamics in Amber: Implementation, Benchmarking and Analysis.

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