A Comprehensive Analysis of Protein Data Bank reveals Low Desolvation Penalty in π-Cation System

Abstract Cation-π interactions widely exist between ligand-protein interfaces, attracting much attention in molecular recognition in recent years. Interactions named cation-π and π-cation (cationic vs arene small molecular ligands) shall be separately considered in drug and pesticide design process. The two interactions involved in ligands and protein pockets may differ in energy features and therefore offers significant inspiration for drug and pesticide design. However, an in-depth study on differences between cation-π and π-cation systems from an energy perspective is still lacking. In this study, we calculated and compared cation-π and π-cation systems in terms of physicochemical properties of ligand/protein and solvation effect. It seems that the desolvation penalty of the cation-π systems was relatively higher than the π-cation pairs, even though these interactions both can improve the ligand activity. This is the reason for evolution converged on π-cation interactions in the cation-π-mediated proteins. The π-cation interaction facilitating the inhalation of ligand to the pocket may provide a new sight for the molecular design of pharmaceuticals and pesticides.