The voltage sensor deactivation barrier is altered by substitutions in the hydrophobic core
(English)Manuscript (preprint) (Other academic)
The gating of voltage-gated ion channels is caused by the arginine-rich S4 helix of the voltage sensor moving in response to an external potential. Exactly how this is accomplished is not yet fully known, but several studies now indicate S4 transiently adopts 310-conformation to facilitate the process. Here, we combine modeling of intermediate states based on experimental constraints with systematic in silico mutagenesis and free energy calculations to identify metastable states and characterize the energetics when moving between them. We show that states very close to the X-ray structure can be obtained with steered simulations starting from the intermediate state, and that several residues in the narrow hydrophobic band in the middle of the voltage sensor contribute to the free energy between the activated and intermediate states. The single most important is the structural barrier caused by the aromatic ring of F233. Substitution for smaller amino acids reduces the translation cost signi cantly, while introduction of a larger ring increases it, both con rming experimental activation shift results. In fact, the rigid ring appears to determine the barrier for the voltage sensor gating process, with a close interaction between the ring rotation and the arginine barrier crossing.
Condensed Matter Physics
IdentifiersURN: urn:nbn:se:kth:diva-34853OAI: oai:DiVA.org:kth-34853DiVA: diva2:423873