Possible interaction mechanism for quaternary ammonium (QA) ions binding to potassium channels: density functional theory and MP2 studies on the interaction between phenol and ammonium cation†

Abstract

Tetraethylammonium (TEA) and other quaternary ammonium (QA) ions are potent blockers of potassium channels. In order to shed light on the blockade mechanism of QA ions, we have carried out a series of computations on the phenol–ammonium model with density functional theory (DFT) and Möller–Plesset second order perturbation (MP2) methods at levels of 6-31G* and 6-31G** basis sets. NH–aromatic π interaction and NH–OH hydrogen bond interaction, which are important in biological systems, are responsible for the binding of NH₄⁺ to phenol. From analysis of structures, energies, charge populations and transition state features, both the cation–π interaction and hydrogen bond or electrostatic interaction between QAs and the key amino acid residues at the entryways of K⁺ channels are seen to be significant in the blockade mechanism of QA ions.