Constant pH Molecular Dynamics in Explicit Solvent with λ-Dynamics.

pH is an important parameter in condensed-phase systems, because it determines the protonation state of titratable groups and thus influences the structure, dynamics, and function of molecules in solution. In most force field simulation protocols, however, the protonation state of a system (rather than its pH) is kept fixed and cannot adapt to changes of the local environment. Here, we present a method, implemented within the MD package GROMACS, for constant pH molecular dynamics simulations in explicit solvent that is based on the λ-dynamics approach. In the latter, the dynamics of the titration coordinate λ, which interpolates between the protonated and deprotonated states, is driven by generalized forces between the protonated and deprotonated states. The hydration free energy, as a function of pH, is included to facilitate constant pH simulations. The protonation states of titratable groups are allowed to change dynamically during a simulation, thus reproducing average protonation probabilities at a certain pH. The accuracy of the method is tested against titration curves of single amino acids and a dipeptide in explicit solvent.