Systematic Improvement of the Performance of Machine Learning Scoring Functions by Incorporating Features of Protein-Bound Water Molecules

Water molecules at the ligand–protein interfaces play crucial roles in the binding of the ligands, but the behavior of protein-bound water is largely ignored in many currently used machine learning (ML)-based scoring functions (SFs). In an attempt to improve the prediction performance of existing ML-based SFs, we estimated the water distribution with a HydraMap (HM) method and then incorporated the features extracted from protein-bound waters obtained in this way into three ML-based SFs: RF-Score, ECIF, and PLEC. It was found that a combination of HM-based features can consistently improve the performance of all three SFs, including their scoring, ranking, and docking power. HydraMap-based features show consistently good performance with both crystal structures and docked structures, demonstrating their robustness for SFs. Overall, HM-based features, which are a statistical representation of hydration sites at protein–ligand interfaces, are expected to improve the prediction performance for diverse SFs.