Molecular dynamics simulations of neuronal nicotinic acetylcholine receptor allosteric modulation

The neuronal nicotinic acetylcholine receptor is a key experimental system for studying allosteric modulation, including by clinically useful drugs. Diverse physiological responses manifest from differential assembly of nicotinic receptor subunits (α2−α10 and β2−β4) into homo- or heteropentamers. An extensive body of electrophysiology data has demonstrated that the anthelmintic compounds morantel and oxantel display limited partial-agonist activity at mammalian nicotinic receptors, but are positive allosteric modulators of α3β2 receptors, while oxantel is a negative modulator of α4β2 receptors. Largely through mutation analyses, we have identified amino acid determinants of specificity for the compounds, as well as elements of the receptor extracellular domain that crosstalk between functional sites. Here, we initiated a systematic comparison of subtype specificity, based on molecular modeling and simulations of published cryo-electron microscopy structures and homology models. Preliminary results indicate differential movements in the C loop of orthosteric versus allosteric sites, involvement of key residues predicted to influence specificity in interactions with ligands, and inter- and intra-subunit functional connectivity assessed by network analysis. These studies promise to elucidate allosteric modulation mechanisms that govern site-to-site and ligand-to-gate communication in nicotinic and related receptors.