Protein-Ligand CH-π Interactions: Structural Informatics, Energy Function Development, and Docking Implementation

Here, we develop an empirical energy function based on quantum mechanical data for the interaction between methane and benzene that captures the contribution from CH-π interactions. Such interactions are frequently observed in protein-ligand crystal structures, particularly for carbohydrate ligands, but have been hard to quantify due to the absence of a model for CH-π interactions in typical molecular mechanical force fields or docking scoring functions. The CH-π term was added to the AutoDock Vina (AD VINA) scoring function enabling its performance to be evaluated against a cohort of more than 1600 occurrences in 496 experimental structures of protein-ligand complexes. By employing a conformational grid search algorithm, inclusion of the CH-π term was shown to improve the prediction of the preferred orientation of flexible ligands in protein-binding sites and to enhance the detection of carbohydrate-binding sites that display CH-π interactions. Last but not least, this term was also shown to improve docking performance for the CASF-2016 benchmark set and a carbohydrate set.