Protein-protein interactions play an important role in many cellular processes. The interactions are either through direct contacts between two binding partners or mediated by water molecules. Both direct contacts and water-mediated interactions are crucial to the formation of a protein-protein complex. We developed a novel strategy to predict both direct and water-mediated interactions by combining protein-protein docking, protein-ligand docking and molecular dynamics (MD) simulations. Specifically, for a given pair of protein structures, either experimentally determined or constructed by homology modeling, the conformational space was exhaustively sampled by a FFT-based docking program. The created models were evaluated and ranked by an atomic, statistical potential-based scoring function, followed by clustering with backbone RMSDs. Up to 10 models were selected as the initial protein-protein structures for MD simulations in explicit solvent. For each model, water molecules near the interface were clustered based on snapshots from up to 5 independent equilibrated trajectories. The water molecule closest to the geometric center of a cluster, referred to as the clustered water molecule, was kept for each cluster. The protein-protein complex structure from the snapshots involving a large number of contacts and few clashes with the clustered water molecules was kept as an initial protein-protein-water complex. Then, protein-ligand docking was employed for a parallel search for water molecules near the protein-protein interface for the same protein-protein-water complex. Specifically, after the removal of the water molecules from the complex, a water probe was docked into the protein-protein interface, with an emphasis on hydrogen bonding interactions. The water molecules generated by ligand docking and the clustered water molecules generated by MD simulations were merged, referred to as the predicted structural water molecules. The resulting protein-protein-water complex was refined by MD simulations with restrictions on the predicted structural water molecules and protein backbone atoms. The structure from the last snapshot of the equilibrated trajectory was used as the predicted protein-protein-water complex structure. This systematic, hierarchical approach can be applied to the prediction of both direct and water-mediated interactions in protein-protein complexes.

Predicting direct and water-mediated interactions in protein-protein complexes

2019 Fall National Meeting

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