Accelerating Solvent Dynamics with Replica Exchange for Improved Free Energy Sampling

Molecular reactions in solution typically involve solvent exchange; for example, a surface must partly desolvate for a molecule to adsorb onto it. When these reactions are simulated, slow solvent dynamics can limit the sampling of configurations and reduce the accuracy of free energy estimates. Here, we combine Hamiltonian replica exchange (HREX) with well-tempered metadynamics (WTMD) to accelerate the sampling of solvent configurations orthogonal to the collective variable space. We compute the formation free energy of a carbonate vacancy in the calcite-water interface and find that the combination of WTMD with HREX significantly improves the sampling relative to WTMD without HREX.