Continuous Constant pH Molecular Dynamics in Explicit Solvent with pH-Based Replica Exchange

Abstract

A computational tool that offers accurate pKa values and atomically detailed knowledge of protonation-coupled conformational dynamics is valuable for elucidating mechanisms of energy transduction processes in biology, such as enzyme catalysis and electron transfer as well as proton and drug transport. Toward this goal we present a new technique of embedding continuous constant pH molecular dynamics within an explicit-solvent representation. In this technique we make use of the efficiency of the generalized-Born (GB) implicit-solvent model for estimating the free energy of protein solvation while propagating conformational dynamics using the more accurate explicit-solvent model. Also, we employ a pH-based replica exchange scheme to significantly enhance both protonation and conformational state sampling. Benchmark data of five proteins including HP36, NTL9, BBL, HEWL, and SNase yield an average absolute deviation of 0.53 and a root mean squared deviation of 0.74 from experimental data. This level of accuracy is obtained with 1 ns simulations per replica. Detailed analysis reveals that explicit-solvent sampling provides increased accuracy relative to the previous GB-based method by preserving the native structure, providing a more realistic description of conformational flexibility of the hydrophobic cluster, and correctly modeling solvent mediated ion-pair interactions. Thus, we anticipate that the new technique will emerge as a practical tool to capture ionization equilibria while enabling an intimate view of ionization coupled conformational dynamics that is difficult to delineate with experimental techniques alone.

Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH

“…We also demonstrated that the potential artifacts are negligible in the hybrid-solvent scheme where GB model is applied to propagating the titration coordinates. 15 However, a varying net charge is a major issue that needs to be addressed for developing an accurate CpHMD method based on the explicit-solvent model. If neglected, overestimation of electrostatic coupling between ionizable sites may occur, as will be shown in Sec.…”

“…14 Recently, the method was extended to conformational sampling in explicit solvent while propagating the titration coordinates via GB calculations, in an attempt to circumvent the conformational bias of implicit-solvent models while retaining the ability to quickly evaluate solvation free energies. 15 This hybrid-solvent scheme, combined with a pH-based replicaexchange protocol, 15 has been shown to offer more realistic pH-dependent conformational sampling and more accurate pK a prediction for proteins 15 as well as surfactant micelles. 16 Most recently, two groups have reported on the development of CpHMD techniques based solely on explicit-solvent models and testing on small model systems.…”

“…Residual net charge is not a concern for methods that use GB implicit-solvent model for computing forces on λ particles (titration coordinates). 14,15 However, it needs to be compensated in fully explicit-solvent simulations. Here we present a technique which couples proton titration with simultaneous ionization or neutralization of a co-ion in solution.…”

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

“…[47][48][49] Recent studies have shown that CPHMD is a reliable and robust method that is capable of predicting pK a values in a variety of biomolecular systems. [50][51][52][53][54][55][56] Thus, to uncover the pHdependent residues in the CIRV p19 protein involved in siRNA binding stability, we have carried out CPHMD simulations [44][45][46] of the p19 protein dimer in both holo (siRNA-bound) and apo (siRNAfree) forms and determined the pK a values for all titratable residues. These results were then used to calculate the pH-dependent siRNA binding stability profile and corresponding pH-dissociation constant profile.…”

Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems

“…Processes such as the solvent-mediated proton transfer in close compartments could be fully described. Works carried out by Wallace and Shen (2011) and Swails et al (2014) demonstrated that the RMSD can decrease, respectively, from 0.93 to 0.84 and 1.32 to 0.92 when replacing the implicit solvent by an explicit description. The study was done with hen egg white lysozyme (PDB ids were 2LZT and 3LZT, respectively).…”