Application of Explicit-Solvent Constant ph Molecular Dynamics to Proteins

Solution pH is a critical factor in biological and chemical processes. To enable molecular simulations of proton-coupled dynamics in these processes, the continuous constant pH molecular dynamics (CpHMD) method has been developed. Recently, we extended the CpHMD framework to explicit-solvent simulations and tested on the titration of a series of aliphatic dicarboxylic acids. Here we applied the method to several proteins including 36-residue HP36, 45-residue BBL, 56-residue NTL9, and 129-residue HEWL. The calculated pKa's have a root mean square deviation below one pH unit from experiment. This accuracy is comparable to the hybrid-solvent CpHMD, where the Generalized-Born (GB) implicit-solvent model is used to propagate titration coordinates while explicit-solvent is used to propagate conformational degrees of freedom. However, the explicit-solvent method avoids the artifacts and limitations of the GB model. This work demonstrates that the explicit-solvent CpHMD method paves the way for realizing pH-controlled all-atom MD simulations.