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.

中文翻译：

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内耳机械转导通道 TMC1 模型的硅电生理学

内耳感觉毛细胞在机械传导过程中将来自声音和头部运动的机械刺激转化为电信号。内耳机械转导装置的所有分子成分的鉴定正在进行中；然而，有强有力的证据表明 TMC1 和 TMC2 是复合物的成孔亚基。我们提出了分子动力学模拟，探测基于相关 TMEM16 蛋白的两种不同结构构建的 TMC1 模型的离子传导。与大多数通道不同，TMC1 模型不显示中心孔。相反，这些模型在不同电压下的膜环境中的模拟揭示了一种外周渗透途径，该途径暴露于脂质，并显示出与毛细胞中测得的速率相当的阳离子渗透率。此外，我们的分析表明 TMC1 门控机制涉及蛋白质构象变化和张力诱导的脂质介导的孔扩大。这些结果提供了对听力和平衡必不可少的毛细胞机械转导通道的离子传导和激活机制的见解。