Including explicit water molecules as part of the protein structure in MM/PBSA calculations.

Water is the natural medium of molecules in the cell and plays an important role in protein structure, function and interaction with small molecule ligands. However, the widely used molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method for binding energy calculation does not explicitly take account of water molecules that mediate key protein-ligand interactions. We have developed a protocol to include water molecules that mediate ligand-protein interactions as part of the protein structure in calculation of MM/PBSA binding energies (a method we refer to as water-MM/PBSA) for a series of JNK3 kinase inhibitors. Improved correlation between water-MM/PBSA binding energies and experimental IC50 values was obtained compared to that obtained from classical MM/PBSA binding energy. This improved correlation was further validated using sets of neuraminidase and avidin inhibitors. The observed improvement, however, appears to be limited to systems in which there are water-mediated ligand-protein hydrogen bond interactions. We conclude that the water-MM/PBSA method performs better than classical MM/PBSA in predicting binding affinities when water molecules play a direct role in mediating ligand-protein hydrogen bond interactions.