Altered Pore Composition and Flexibility in a Deafness-Associated TMC1 Variant: Insights from Molecular Dynamics Simulations.

Transmembrane channel-like protein 1 (TMC1) forms the pore of the mechanotransduction channel in cochlear and vestibular hair cells, converting mechanical stimuli from sound and head movements into electrochemical signals. Recent evidence supports a dimeric structure for TMC1, with each monomer harboring an independent ion-conducting pore. The p.(M654V) variant, in which methionine 654 is substituted with valine, is associated with non-syndromic autosomal recessive deafness. In the present work, we used molecular dynamics (MD) simulations to compare the structural and biophysical properties of the wild-type and M654V-TMC1 variants, providing atomistic-level insights into subtle alterations in the mechanotransduction system. Our analysis reveals specific alterations in pore size, lipid composition of the pore walls, and the electrostatic environment. The results suggest that the two monomers function independently and underscore the critical role of lipids in shaping the pore architecture. Potential molecular mechanisms of M654V-associated pathogenicity include disrupted local interactions between transmembrane α-helices and residue 654, leading to reduced pore flexibility, a shifted choke point, and fewer lipid molecules incorporated into the pore walls. These findings provide mechanistic insights into TMC1 function and its impairment in deafness-associated variants.