Potential of mean force of water–proton bath and molecular dynamic simulation of proteins at constant pH

An advanced implicit solvent model of water–proton bath for protein simulations at constant pH is presented. The implicit water–proton bath model approximates the potential of mean force of a protein in water solvent in a presence of hydrogen ions. Accurate and fast computational implementation of the implicit water–proton bath model is developed using the continuum electrostatic Poisson equation model for calculation of ionization equilibrium and the corrected MSR6 generalized Born model for calculation of the electrostatic atom–atom interactions and forces. Molecular dynamics (MD) method for protein simulation in the potential of mean force of water–proton bath is developed and tested on three proteins. The model allows to run MD simulations of proteins at constant pH, to calculate pH‐dependent properties and free energies of protein conformations. The obtained results indicate that the developed implicit model of water–proton bath provides an efficient way to study thermodynamics of biomolecular systems as a function of pH, pH‐dependent ionization‐conformation coupling, and proton transfer events. © 2012 Wiley Periodicals, Inc.