Enhanced Grand Canonical Sampling of Occluded Water Sites Using Nonequilibrium Candidate Monte Carlo

Water molecules play a key role in many biomolecular systems, particularly when bound at protein-ligand interfaces. However, molecular simulation studies on such systems are hampered by the relatively long time scales over which water exchange between a protein and solvent takes place. Grand canonical Monte Carlo (GCMC) is a simulation technique that avoids this issue by attempting the insertion and deletion of water molecules within a given structure. The approach is constrained by low acceptance probabilities for insertions in congested systems, however. To address this issue, here, we combine GCMC with nonequilibium candidate Monte Carlo (NCMC) to yield a method that we refer to as grand canonical nonequilibrium candidate Monte Carlo (GCNCMC), in which the water insertions and deletions are carried out in a gradual, nonequilibrium fashion. We validate this new approach by comparing GCNCMC and GCMC simulations of bulk water and three protein binding sites. We find that not only is the efficiency of the water sampling improved by GCNCMC but that it also results in increased sampling of ligand conformations in a protein binding site, revealing new water-mediated ligand-binding geometries that are not observed using alternative enhanced sampling techniques.

Automated summary

Water molecules are crucial in biomolecular systems, especially at protein-ligand interfaces. However, simulating such systems is challenging due to slow water exchange between protein and solvent. To overcome this, the authors combine grand canonical Monte Carlo (GCMC) with nonequilibrium candidate Monte Carlo (NCMC) to develop grand canonical nonequilibrium candidate Monte Carlo (GCNCMC). This approach improves water sampling efficiency and enables the exploration of new ligand-binding geometries mediated by water.