BPS2026 – Comparison of distinct allosteric modulator sites of nicotinic receptors by molecular dynamics

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that mediate intercellular communication throughout the nervous system. Various subtypes of the neuronal nAChRs are localized in their roles in cognitive processes and implicated in neurological diseases, as well as in nicotine addiction. Previous work from our lab found that the allosteric modulators morantel and oxantel both potentiate the α3β2 subtype, while morantel is ineffective on and oxantel inhibits the α4β2 subtype. Motivated by such results, we used molecular dynamics (MD) simulations to study the effect of morantel and oxantel on neuronal nAChR subtypes α3β2 and α4β2, in two inequivalent allosteric sites occurring in the extracellular domain of the (α) 2 (β) 3 stoichiometry. Multifaceted comparison of 20 systems that differ in receptor subtype and in agonist and modulator liganded states reveals asymmetric conformational changes of the subunits in the course of simulations. We observe differences in the C loop movement between subunits in each allosteric site and the orthosteric sites bound with ACh; such results underscore the allosteric communication between ligand binding sites. Protein-ligand interaction analysis shows variances in the type and strength of interactions, pointing toward sources of ligand binding and modulation specificity, aligning with electrophysiology results from point mutations of the receptors. These results will enable us to expand the scope of our studies, employing network analysis and simulations of membrane-bound receptors in future work.