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.