Exploration of Interfacial Hydration Networks of Target-Ligand Complexes.

Interfacial hydration strongly influences interactions between biomolecules. For example, drug–target complexes are often stabilized by hydration networks formed between hydrophilic residues and water molecules at the interface. Exhaustive exploration of hydration networks is challenging for experimental as well as theoretical methods due to high mobility of participating water molecules. In the present study, we introduced a tool for determination of the complete, void-free hydration structures of molecular interfaces. The tool was applied to 31 complexes including histone proteins, a HIV-1 protease, a G-protein-signaling modulator, and peptide ligands of various lengths. The complexes contained 344 experimentally determined water positions used for validation, and excellent agreement with these was obtained. High-level cooperation between interfacial water molecules was detected by a new approach based on the decomposition of hydration networks into static and dynamic network regions (subnets). Besides ...