Constant pH Simulations In Explicit Solvent Using The Lambda-Dynamics Approach

pH is an important parameter in condensed phase systems as it determines the protonation state of ionizable groups and consequently influences the structure, dynamics and function of molecules in solution. In the past ten years, few approaches have been applied to model the pH of a solution in the framework of Molecular Dynamics (MD) and Monte Carlo (MC) simulation methods. These include stochastic and mean field approximation methods to model the (de)protonation events and methods based on the lambda-dynamics approach, where the dynamics of the titration coordinate lambda is driven by the free energy gradient between the protonated and deprotonated states. In particular, the latter approach was so far limited to implicit solvent. We present here a method for constant pH simulations in explicit solvent that is based on the lambda-dynamics approach. The method has been implemented in the MD package Gromacs. The titration curve of single amino acids and small peptides and the shift in the pKa of an active site glutamic acid in the enzyme triosephosphate isomerase were correctly predicted. This preliminary tests suggest that the approach can be applied to simulate (bio)molecules with multiple titrating sites at constant pH.