Molecular simulation with variable protonation states at constant pH

Abstract

A new method is presented for performing molecular simulations at constant pH. The method is a Monte Carlo procedure where trial moves consist of relatively short molecular dynamics trajectories, using a time-dependent potential energy that interpolates between the old and new protonation states. Conformations and protonation states are sampled from the correct statistical ensemble independent of the trial-move trajectory length, which may be adjusted to optimize efficiency. Because moves are not instantaneous, the method does not require the use of a continuum solvation model. It should also be useful in describing buried titratable groups that are not directly exposed to solvent, but have strong interactions with neighboring hydrogen bond partners. The feasibility of the method is demonstrated for a simple test case: constant-pH simulations of acetic acid in aqueous solution with an explicit representation of water molecules.