Prediction of Ordered Water Molecules in Protein BindingSites from Molecular Dynamics Simulations: The Impact of Ligand Bindingon Hydration Networks

摘要

Water plays a major role in ligand binding and is attracting increasing attention in structure-based drug design. Water molecules can make large contributions to binding affinity by bridging protein–ligand interactions or by being displaced upon complex formation, but these phenomena are challenging to model at the molecular level. Herein, networks of ordered water molecules in protein binding sites were analyzed by clustering of molecular dynamics (MD) simulation trajectories. Locations of ordered waters (hydration sites) were first identified from simulations of high resolution crystal structures of 13 protein–ligand complexes. The MD-derived hydration sites reproduced 73% of the binding site water molecules observed in the crystal structures. If the simulations were repeated without the cocrystallized ligands, a majority (58%) of the crystal waters in the binding sites were still predicted. In addition, comparison of the hydration sites obtained from simulations carried out in the absence of ligands to those identified for the complexes revealed that the networks of ordered water molecules werepreserved to a large extent, suggesting that the locations of watersin a protein–ligand interface are mainly dictated by the protein.Analysis of >1000 crystal structures showed that hydration sitesbridgedprotein–ligand interactions in complexes with different ligands,and those with high MD-derived occupancies were more likely to correspondto experimentally observed ordered water molecules. The results demonstratethat ordered water molecules relevant for modeling of protein–ligandcomplexes can be identified from MD simulations. Our findings couldcontribute to development of improved methods for structure-basedvirtual screening and lead optimization.