Efficient Sampling of Cavity Hydration in Proteins with Nonequilibrium Grand Canonical Monte Carlo and Polarizable...

Prediction of the hydration levels of protein cavities and active sites is important to both mechanistic analysis and ligand design. Due to the unique microscopic environment of these buried water molecules, a polarizable model is expected to be crucial for an accurate treatment of protein internal hydration in simulations. Here we adapt a nonequilibrium candidate Monte Carlo approach for conducting grand canonical Monte Carlo simulations with the Drude polarizable force field. The GPU implementation enables the efficient sampling of internal cavity hydration levels in biomolecular systems. We also develop an enhanced sampling approach referred to as B-walking, which satisfies detailed balance and readily combines with grand canonical integration to efficiently calculate quantitative binding free energies of water to protein cavities. Applications of these developments are illustrated in a solvent box and the polar ligand binding site in trypsin. Our simulation results show that including electronic polarization leads to a modest but clear improvement in the description of water position and occupancy compared to the crystal structure. The B-walking approach enhances the range of water sampling in different chemical potential windows and thus improves the accuracy of water binding free energy calculations.