Title : Molecular simulation of the Kv7.4[?S269] mutant channel reveals that ion conduction in the cavity is perturbed due to hydrophobic gating

Authors : Md Harunur Rashid

Abstract : Mutations in the voltage-gated potassium channel Kv7.4 (encoded as KCNQ4) lead to the early onset of non-syndromic hearing loss, which is significant during language acquisition. The deletion of the S269 pore residue (genetic ? mutation) in Kv7.4 has been reported to be associated with hearing loss. So far, there is no mechanistic understanding of how this mutation modulates channel function. To understand the role of S269 in ion conduction, we performed molecular dynamics simulations for both wild type and ?S269 mutant channels. Simulations indicate that the ?S269 mutation suppresses the fluctuations in the neighboring Y269 residue and thereby consolidates the ring formed by I307 and F310 residues in the adjacent S6 helixes in the cavity region. We show that the long side chains of I307 near the entrance to the cavity form a hydrophobic gate. Comparison of the free energy profiles of a cavity ion in Kv7.4 and Kv7.4[?S269] channels reveals a sizable energy barrier in the latter case, which suppresses ion conduction. Thus the simulation studies reveal that the hydrophobic gate resulting from the ?S269 mutation appears to be responsible for sensorineural hearing loss.

Journal : Biochemistry and Biophysics Reports Volume : 25 Year : 2021 Issue : 100879
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