Comprehensive 3D-RISM analysis of the hydration of small molecule binding sites in ligand-free protein structures.

Hydration is a critical factor in the ligand binding process. Herein, to examine the hydration states of ligand binding sites, the three-dimensional distribution function for the water oxygen site, gO (r), is computed for 3,706 ligand-free protein structures based on the corresponding small molecule-protein complexes using the 3D-RISM theory. For crystallographic waters (CWs) close to the ligand, gO (r) reveals that several CWs are stabilized by interaction networks formed between the ligand, CW, and protein. Based on the gO (r) for the crystallographic binding pose of the ligand, hydrogen bond interactions are dominant in the highly hydrated regions while weak interactions such as CH-O are dominant in the moderately hydrated regions. The polar heteroatoms of the ligand occupy the highly hydrated and moderately hydrated regions in the crystallographic (correct) and wrongly docked (incorrect) poses, respectively. Thus, the gO (r) of polar heteroatoms may be used to distinguish the correct binding poses.