Delineation of the Unbinding
Pathway of α-Conotoxin
ImI from the α7 Nicotinic Acetylcholine Receptor
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Abstract
α-Conotoxins potently and specifically inhibit
isoforms of
nicotinic acetylcholine receptors (nAChRs) and are used as molecular
probes and as drugs or drug leads. Interactions occurring during binding
and unbinding events are linked to binding kinetics, and knowledge
of these interactions could help in the development of α-conotoxins
as drugs. Here, the unbinding process for the prototypical α-conotoxin
ImI/α7-nAChR system was investigated theoretically, and three
exit routes were identified using random accelerated molecular dynamics
simulations. The route involving the smallest conformation perturbation
was further divided into three subpathways, which were studied using
steered molecular dynamics simulations. Of the three subpathways,
two had better experimental support and lower potential of mean force,
indicating that they might be sampled more frequently. Additionally,
these subpathways were supported by previous experimental studies.
Several pairwise interactions, including a cation-π interaction
and charge and hydrogen bond interactions, were identified as potentially
playing important roles in the unbinding event