Cation-π interactions are common in biological systems, in particular ligand-gated ion channels (LGICs). Our own studies, in addition to more recent structural studies, have revealed the aromatic box as a common motif for binding cationic ligands. With the aim of understanding the nature of the aromatic box, several computational methods were evaluated for their ability to reproduce experimental 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 number of different cations (sodium, potassium, ammonium, tetramethylammonium, and guanidinium) was studied. In addition, the binding of the organic cations NH4+ and NMe4+ to ab initio generated aromatic boxes as well as examples of aromatic boxes from a number of protein crystal structures was investigated. In addition, we have performed a study of the intrinsic distance dependence of the cation-π interaction. We find that multiple aromatic 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.

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

251st National Meeting (2016)

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