Combining 3D-RISM calculation with hydropathic character for water selection: an application in docking with flexible explicit water

Docking and virtual screening with explicit water has become a hot topic within the docking community in the past decade. It was suggested that the bridging water molecules, existed between the ligand and the receptor, are important contributors to binding free energy. Multiple methods are since developed, either through direct evaluation or scoring of crystal waters, or predictions for water positions when crystal waters are in absence. However, the likelihood of introducing human bias increases during the process of water selection. Moreover, wrong choices about water molecules will result in fault screening, giving ineffective candidates. Therefore, in our work, we have combined a well-established water-predicting method, 3D-RISM, and a relatively simple and efficient water selection criteria by evaluating hydropathic characteristic of water molecules. This flow of work has allowed automatic selection of water molecules between protein-ligand or protein-protein interface. We have observed optimistic results in predicting crystal water positions within the binding pocket using several benchmark systems. We will further combine these steps with flexible water docking, included in the PLANTS docking package, to improve virtual screening with explicit waters both in efficiency and accuracy.