Molecular Recognition in Nicotinic Acetylcholine Receptors: The Importance of π−Cation Interactions

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Abstract
We explore the significance of π−cation interactions in the binding of ligands to nicotinic acetylcholine receptors. Specifically, the Austin method of semiempirical molecular orbital theory is utilized to estimate the interaction of aromatic amino acid side chains with the cation-containing heterocyclic ring fragments of nicotinic ligands. Variational interaction energies (Ei) of side chain−ligand fragment pairs are shown to be distance-dependent and follow a Morse-like potential function. The tryptophan side chain shows the most pronounced interaction with the cation fragments, followed by tyrosine and phenylalanine. For a given side chain, cationic fragments exhibit characteristically different Ei profiles, with the azabicyclo[2.2.1]heptane fragment of the potent nicotinic ligand epibatidine eliciting the greatest 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 heteropentameric (α4β2) and homopentameric (α7) 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.