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Constant-pH Brownian Dynamics Simulations of a Protein near a Charged Surface.

ABSTRACT: We have developed a rigid-body Brownian dynamics algorithm that allows for simulations of a globular protein suspended in an ionic solution confined by a charged planar boundary, with an explicit treatment of pH-dependent protein protonation equilibria and their couplings to the electrostatic potential of the plane. Electrostatic interactions are described within a framework of the continuum Poisson-Boltzmann model, whereas protein-plane hydrodynamic interactions are evaluated based on analytical expressions for the position- and orientation-dependent near-wall friction tensor of a spheroid. The algorithm was applied to simulate near-surface diffusion of lysozyme in solutions having pH in the range 4-10 and ionic strengths of 10 and 150 mM. As a reference, we performed Brownian dynamics simulations in which the protein is assigned a fixed, most probable protonation state, appropriate for given solution conditions and unaffected by the presence of the charged plane, and Brownian dynamics simulations in which the protein probes possible protonation states with the pH-dependent probability, but these variations are not coupled to the electric field generated by the boundary. We show that electrostatic interactions with the negatively charged plane substantially modify probabilities of different protonation states of lysozyme and shift protonation equilibria of both acidic and basic amino acid side chains toward higher pH values. Consequently, equilibrium energy distributions, equilibrium position-orientation distributions, and functions that characterize rotational dynamics, which for a protein with multiple ionization sites, such as lysozyme, in the presence of a charged obstacle are pH-dependent, are significantly affected by the approach taken to incorporate the solution pH into simulations.

SUBMITTER: Antosiewicz JM

PROVIDER: S-EPMC7689933 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Constant-pH Brownian Dynamics Simulations of a Protein near a Charged Surface.

Antosiewicz Jan M JM Długosz Maciej M

ACS omega 20201112 46

We have developed a rigid-body Brownian dynamics algorithm that allows for simulations of a globular protein suspended in an ionic solution confined by a charged planar boundary, with an explicit treatment of pH-dependent protein protonation equilibria and their couplings to the electrostatic potential of the plane. Electrostatic interactions are described within a framework of the continuum Poisson-Boltzmann model, whereas protein-plane hydrodynamic interactions are evaluated based on analytica ...[more]

PMID: 33251463

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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

Constant-pH Brownian Dynamics Simulations of a Protein near a Charged Surface.

Publications

Constant-pH Brownian Dynamics Simulations of a Protein near a Charged Surface.

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