Dataset Information

Catalytic Site pKa Values of Aspartic, Cysteine, and Serine Proteases: Constant pH MD Simulations.

ABSTRACT: Enzymatic function and activity of proteases is closely controlled by the pH value. The protonation states of titratable residues in the active site react to changes in the pH value, according to their pKa, and thereby determine the functionality of the enzyme. Knowledge of the titration behavior of these residues is crucial for the development of drugs targeting the active site residues. However, experimental pKa data are scarce, since the systems' size and complexity make determination of these pKa values inherently difficult. In this study, we use single pH constant pH MD simulations as a fast and robust tool to estimate the active site pKa values of a set of aspartic, cysteine, and serine proteases. We capture characteristic pKa shifts of the active site residues, which dictate the experimentally determined activity profiles of the respective protease family. We find clear differences of active site pKa values within the respective families, which closely match the experimentally determined pH preferences of the respective proteases. These shifts are caused by a distinct network of electrostatic interactions characteristic for each protease family. While we find convincing agreement with experimental data for serine and aspartic proteases, we observe clear deficiencies in the description of the titration behavior of cysteines within the constant pH MD framework and highlight opportunities for improvement. Consequently, with this work, we provide a concise set of active site pKa values of aspartic and serine proteases, which could serve as reference for future theoretical as well as experimental studies.

SUBMITTER: Hofer F

PROVIDER: S-EPMC7312390 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Catalytic Site pKa Values of Aspartic, Cysteine, and Serine Proteases: Constant pH MD Simulations.

Hofer Florian F Kraml Johannes J Kahler Ursula U Kamenik Anna S AS Liedl Klaus R KR

Journal of chemical information and modeling 20200529 6

Enzymatic function and activity of proteases is closely controlled by the pH value. The protonation states of titratable residues in the active site react to changes in the pH value, according to their pKa, and thereby determine the functionality of the enzyme. Knowledge of the titration behavior of these residues is crucial for the development of drugs targeting the active site residues. However, experimental pKa data are scarce, since the systems' size and c ...[more]

PMID: 32348143

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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

Catalytic Site pKa Values of Aspartic, Cysteine, and Serine Proteases: Constant pH MD Simulations.

Publications

Catalytic Site p<i>K</i><sub>a</sub> Values of Aspartic, Cysteine, and Serine Proteases: Constant pH MD Simulations.

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