Water Network-Augmented Two-State Model for Protein-Ligand Binding Affinity Prediction.

Water network rearrangement from the ligand-unbound state to the ligand-bound state is known to have significant effects on the protein-ligand binding interactions, but most of the current machine learning-based scoring functions overlook these effects. In this study, we endeavor to construct a comprehensive and realistic deep learning model by incorporating water network information into both ligand-unbound and -bound states. In particular, extended connectivity interaction features were integrated into graph representation, and graph transformer operator was employed to extract features of the ligand-unbound and -bound states. Through these efforts, we developed a water network-augmented two-state model called ECIFGraph::HM-Holo-Apo. Our new model exhibits satisfactory performance in terms of scoring, ranking, docking, screening, and reverse screening power tests on the CASF-2016 benchmark. In addition, it can achieve superior performance in large-scale docking-based virtual screening tests on the DEKOIS2.0 data set. Our study highlights that the use of a water network-augmented two-state model can be an effective strategy to bolster the robustness and applicability of machine learning-based scoring functions, particularly for targets with hydrophilic or solvent-exposed binding pockets.