Inspired by the observation that ligand binding stabilizes proteins for crystallography, we tested the hypothesis that cognate interactions in native binding interfaces result in enhanced rigidity that can be computationally distinguished from misdocked complexes. By applying a constraint-counting algorithm to quantify the degrees of freedom in the bond network for a panel of 30 protein complexes, including 11 with corresponding apo structures, the SiteInterlock method showed interfacial rigidification due to bond coupling to be a consistent feature of protein-ligand complexes. Rigidity provides independent information (little correlation) relative to other features commonly used to characterize interfaces.<br/><br/>SiteInterlock’s rigidity score was competitive with the best of a series of existing scoring functions (DOCK6 Amber Score, PoseScore, AutoDock Vina, DSX, and X-Score) in accurately selecting native complexes from panels of dockings, and outperformed most methods when apo protein structures were used. We have gone on to probe in atomistic detail the patterns of hydrogen-bond interactions for a series of 137 non-homologous protein-ligand complexes. The findings indicate surprising polarity of interactions across the binding interface for non-peptidyl ligands, pinpointing specific trends that can readily be used in the design of inhibitors or agonists that better mimic native protein-ligand interactions.

New hallmarks of protein-small molecule binding: Interfacial rigidity and polarity

254th National Meeting (2017)

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