RT Journal Article SR Electronic T1 In Silico Electrophysiology of Inner-Ear Mechanotransduction Channel TMC1 Models JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.09.17.460860 DO 10.1101/2021.09.17.460860 A1 Sanket Walujkar A1 Jeffrey M. Lotthammer A1 Collin R. Nisler A1 Joseph C. Sudar A1 Angela Ballesteros A1 Marcos Sotomayor YR 2021 UL http://biorxiv.org/content/early/2021/09/18/2021.09.17.460860.abstract AB Inner-ear sensory hair cells convert mechanical stimuli from sound and head movements into electrical signals during mechanotransduction. Identification of all molecular components of the inner-ear mechanotransduction apparatus is ongoing; however, there is strong evidence that TMC1 and TMC2 are pore-forming subunits of the complex. We present molecular dynamics simulations that probe ion conduction of TMC1 models built based on two different structures of related TMEM16 proteins. Unlike most channels, the TMC1 models do not show a central pore. Instead, simulations of these models in a membrane environment at various voltages reveal a peripheral permeation pathway that is exposed to lipids and that shows cation permeation at rates comparable to those measured in hair cells. Furthermore, our analyses suggest that TMC1 gating mechanisms involve protein conformational changes and tension-induced lipid-mediated pore widening. These results provide insights into ion conduction and activation mechanisms of hair-cell mechanotransduction channels essential for hearing and balance.Competing Interest StatementThe authors have declared no competing interest.