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

Abstract

We explore the significance of pi-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 (E(i)) 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 E(i) 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 (alpha4beta2) and homopentameric (alpha7) 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.

Aggregate structure of hydroxyproline-rich glycoprotein (HRGP) and HRGP assisted dispersion of carbon nanotubes

“…Firstly, hydrophobic interactions between the repetitive tyrosine blocks; secondly, interactions between positively charged lysine residues and the negatively charged C-terminus; thirdly, lysine residues may also interact with the aromatic rings of the tyrosine residues through cation-p interactions [13,14]; and finally, the Mg 2+ ions undoubtedly promote homophilic associations between the extensively glycosylated Ser-Hyp 4 glycomodules as already demonstrated for Ca 2+ ions (Tan, Sulaiman, Tees and Kieliszewski, unpublished data). At high ionic strength, the electrostatic, cation-p and hydrophobic interactions are screened by the redistribution of ions in solution and thus the condensed aggregates opened up and displayed the random networks of linear fibrils.…”

A potentially novel nicotinic receptor inAplysianeuroendocrine cells

“…1D). We also assessed TMA, which activates nicotinic receptors via the same quaternary ammonium ion motif as acetylcholine (Ascher et al 1978;Schmitt et al 1999). At a level between nicotine and acetylcholine, the TMA-induced depolarization was ϳ24 mV (n ϭ 9) (Fig.…”

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

“…As one HEPES molecule from the crystallization buffer was present within each binding site, it was possible to observe the details of the binding, in particular the p-cation interaction made by Trp 143 of Ls-AChBP (corresponding to aTrp 149 in Torpedo receptor) and the quaternary ammonium of the ligand: this kind of interaction was previously observed in the modeled complex acetylcholinesterase and acetylcholine [236] and hypothesized to have a role in nAChR ligand recognition. [237,238] The availability of the structure of AChBP opened the way to build realistic structural models of nicotinic receptor LBD domain through homology modeling, a computational technique which is based on the alignment between the sequence of a target protein and that of a homologous protein of known structure. To obtain models with significant reliability, lysine scanning mutagenesis experiments have been performed on AChR subunits which determined the orientation of residue side chains toward the hydrophobic core or the hydrophilic surface, thus allowing assignment of correct correspondence between residues in the alignment with AChBP.…”