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Predicting extreme pKa shifts in staphylococcal nuclease mutants with constant pH molecular dynamics.

ABSTRACT: Accurate computational methods of determining protein and nucleic acid pK(a) values are vital to understanding pH-dependent processes in biological systems. In this article, we use the recently developed method constant pH molecular dynamics (CPHMD) to explore the calculation of highly perturbed pK(a) values in variants of staphylococcal nuclease (SNase). Simulations were performed using the replica exchange (REX) protocol for improved conformational sampling with eight temperature windows, and yielded converged proton populations in a total sampling time of 4 ns. Our REX-CPHMD simulations resulted in calculated pK(a) values with an average unsigned error (AUE) of 0.75 pK units for the acidic residues in ? + PHS, a hyperstable variant of SNase. For highly pK(a)-perturbed SNase mutants with known crystal structures, our calculations yielded an AUE of 1.5 pK units and for those mutants based on modeled structures an AUE of 1.4 pK units was found. Although a systematic underestimate of pK shifts was observed in most of the cases for the highly perturbed pK mutants, correlations between conformational rearrangement and plasticity associated with the mutation and error in pK(a) prediction was not evident in the data. This study further extends the scope of electrostatic environments explored using the REX-CPHMD methodology and suggests that it is a reliable tool for rapidly characterizing ionizable amino acids within proteins even when modeled structures are employed.

SUBMITTER: Arthur EJ

PROVIDER: S-EPMC3213318 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Predicting extreme pKa shifts in staphylococcal nuclease mutants with constant pH molecular dynamics.

Arthur Evan J EJ Yesselman Joseph D JD Brooks Charles L CL

Proteins 20111015 12

Accurate computational methods of determining protein and nucleic acid pK(a) values are vital to understanding pH-dependent processes in biological systems. In this article, we use the recently developed method constant pH molecular dynamics (CPHMD) to explore the calculation of highly perturbed pK(a) values in variants of staphylococcal nuclease (SNase). Simulations were performed using the replica exchange (REX) protocol for improved conformational sampling with eight temperature windows, and ...[more]

PMID: 22002886

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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

Predicting extreme pKa shifts in staphylococcal nuclease mutants with constant pH molecular dynamics.

Publications

Predicting extreme pKa shifts in staphylococcal nuclease mutants with constant pH molecular dynamics.

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