Charge-charge and cation- π interactions in ligand binding to G protein-coupled receptors.

To study the importance of charge–charge and cation-π interactions for the binding of positively charged amine ligands to their receptors, the energies of interaction between [(CH₃)₄–N]⁺, [(CH₃)₃–NH]⁺, and [(CH₃)₄–NH₃]⁺ and acetate, as a model of Asp and Glu, and with benzene, as a model of aromatic side chains, were obtained at the MP2/aug-cc-pVDZ level of theory. The free energies of solvation in water were also calculated for the different amines. It was found that, although primary amines form stronger charge–charge interactions with acetate than tertiary or quaternary amines, the difference is not large enough to compensate their higher solvation energy. Quaternary amines show the weakest interaction with acetate. However, their alkyl groups can interact with various aromatic groups, enhancing ligand binding to the receptor. The analysis was completed with MD calculations on amine binding to the G protein-coupled receptors β₂AR and CCR5. The calculations on the model systems were found to be in good agreement with the simulations of the ligand-receptor complexes. [ABSTRACT FROM AUTHOR]