Molecular recognition in nicotinic acetylcholine receptors: The importanceof pi-cation interactions

We explore the significance of pi-cation interactions in the binding of lig ands to nicotinic acetylcholine receptors. Specifically, the Austin method of semiempirical molecular orbital theory is utilized to estimate the inter action of aromatic amino acid side chains with the cation-containing hetero cyclic ring fragments of nicotinic ligands. Variational interaction energie s (E-i) of side chain-ligand fragment pairs are shown to be distance-depend ent and follow a Morse-like potential function. The tryptophan side chain s hows the most pronounced interaction with the cation fragments, followed by tyrosine and phenylalanine. For a given side chain, cationic fragments exh ibit characteristically different E-i profiles, with the azabicyclo[2.2.1]h eptane fragment of the potent nicotinic ligand epibatidine eliciting the gr eatest interaction energy of the study set. Most significantly, the minimum energy values calculated for numerous fragments correlate with the binding affinity of the parent ligands-we show this to be the case for heteropenta meric (alpha 4 beta 2) and homopentameric (alpha 7) nicotinic acetylcholine receptor subtypes. Furthermore, intermolecular distances corresponding to the Morse-like potential minimum also correlate with high-affinity binding. A number of parallel calculations were conducted at the Hartree-Fock 6-31G ** ab initio level of theory in an effort to substantiate these findings.