Blockade of Human 7 Nicotinic Acetylcholine Receptor by -Conotoxin ImI Dendrimer: Insight from Computational Simulations

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are involved in fast synaptic transmission and mediated physiological activities in the nervous system. -Conotoxin ImI exhibits subtype-specific blockade towards homomeric 7 and 9 receptors. In this study, we established a method to build a 2xImI-dendrimer/h (human) 7 nAChR model, and based on this model, we systematically investigated the molecular interactions between the 2xImI-dendrimer and h7 nAChR. Our results suggest that the 2xImI-dendrimer possessed much stronger potency towards h7 nAChR than the -ImI monomer and demonstrated that the linker between -ImI contributed to the potency of the 2xImI-dendrimer by forming a stable hydrogen-bond network with h7 nAChR. Overall, this study provides novel insights into the binding mechanism of -ImI dendrimer to h7 nAChR, and the methodology reported here opens an avenue for the design of more selective dendrimers with potential usage as drug/gene carriers, macromolecular drugs, and molecular probes.