Homology Model and Ligand Binding Interactions of the Extracellular Domain of the Human <i>α</i>4<i>β</i>2 Nicotinic Acetylcholine Receptor

Abstract

Addiction to nicotine, and possibly other tobacco constituents, is a major factor that contributes to the difficulties smokers face when attempting to quit smoking. Amongst the various subtypes of nicotinic acetylcholine receptors (nAChRs), the α 4 β 2 subtype plays an important role in mediating the addiction process. The characterization of human α 4 β 2-ligand binding interactions provides a molecular framework for understanding ligand-receptor interactions, rendering insights into mechanisms of nicotine addiction and may furnish a tool for efficiently identifying ligands that can bind the nicotine receptor. Therefore, we constructed a homology model of human α 4 β 2 nAChR and performed molecular docking and molecular dynamics (MD) simulations to elucidate the potential human α 4 β 2-ligand binding modes for eleven compounds known to bind to this receptor. Residues V96, L97 and F151 of the α 4 subunit and L111, F119 and F121 of the β 2 subunit were found to be involved in hydrophobic interactions while residues S153 and W154 of the α4 subunit were involved in the formation of hydrogen bonds between the receptor and respective ligands. The homology model and its eleven ligand-bound structures will be used to develop a virtual screening program for identifying tobacco constituents that are potentially addictive.