Cation-π interactions: Computational analyses of the aromatic box motif and the fluorination strategy for experimental evaluation of cys-loop receptors and related structures

Abstract

Cation-π interactions are common in biol. systems, in particular ligand- gated ion channels (LGICs). Our own studies, in addn. to more recent structural studies, have revealed the arom. box as a common motif for binding cationic ligands. With the aim of understanding the nature of the arom. box, several computational methods were evaluated for their ability to reproduce exptl. cation-π binding energies. We find the DFT method M06 with the 6-31G(d, p) basis set performs best of several methods tested. The binding of benzene to a no. of different cations (sodium, potassium, ammonium, tetramethylammonium, and guanidinium) was studied. In addn., the binding of the org. cations NH_4+ and NMe_4+ to ab initio generated arom. boxes as well as examples of arom. boxes from a no. of protein crystal structures was investigated. In addn., we have performed a study of the intrinsic distance dependence of the cation- π interaction. We find that multiple arom. residues can contribute to cation binding in a variety of LGICs including ELIC, the glycine receptor, the GABA(A) receptor, and a model of the nicotinic acetylcholine receptor. Progressive fluorination of benzene and indole was studied as well, and binding energies obtained were used to reaffirm the validity of the "fluorination strategy" to study cation-π interactions in vivo.