Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations

Notably,-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (3)2(2)3 nAChR subunit arrangement comprises a pair of3(+)2(ô) and2(+)3(ô) interfaces, and a2(+)2(ô) interface. The2(+)2(ô) interface has been suggested to have higher agonist anity relative to the3(+)2(ô) and2(+)3(ô) interfaces. Nevertheless, the interactions formed by these subunit interfaces with-conotoxins are not well understood. Therefore, in order to address this, we modelled the interactions between-conotoxin LsIA and the32 subtype. The results suggest that the C-terminal carboxylation of LsIA predominantly influenced the enhanced contacts of the conotoxin via residues P7, P14 and C17 on LsIA at the3(+)2(ô) and2(+)3(ô) interfaces. However, this enhancement is subtle at the2(+)2(ô) site, which can compensate the augmented interactions by LsIA at3(+)2(ô) and2(+)3(ô) binding sites. Therefore, the divergent interactions at the individual binding interface may account for the minor changes in binding anity to32 subtype by C-terminal carboxylation of LsIA versus its wild type, as shown in previous experimental results. Overall, these findings may facilitate the development of new drug leads or subtype-selective probes.