机械力敏感离子通道NompC的门控与通透机理研究

机械力感知是生物体对外界物理刺激的一种基础感知能力，人们熟知的触觉、听觉和平衡感等，都是对外界机械力感知的表现，而机械力敏感离子通道在这一感知过程中起到了重要的触发器作用。从果蝇中发现的NompC机械力敏感离子通道，与之前广泛研究的感受膜表面张力的机械力敏感离子通道迥然不同，是目前所知的Tethered机械力敏感离子通道的唯一模型。NompC的结构在2017年得到了解析，但是该离子通道对机械力的响应机理仍不明晰。本项目拟采用大规模分子动力学模拟的方法，系统地研究NompC这一特殊的机械力敏感离子通道受到不同形式的机械力刺激时，将发生怎样的构象变化，从而确定何种形式的机械力能够驱动该离子通道开启。同时，我们也将着重研究该蛋白的Ankyrin Repeats区域的力学性质，包括其杨氏模量，剪变模量，扭转常量，以及机械力在该区域的传递速度等。本项研究预期会发现离子通道的机械力门控的新机理。

Mechano-sensation is one of the most fundamental ability of living organisms to sense external mechanical stimuli. Sensations such as touch, hearing and balance, which are essential for our survival, all started with mechano-sensation. In this process, mechanosensitive ion channels play a critical role as mechano-sensors, which will be opened in response to various forms of mechanical forces, allowing ions to permeate and initiate the downstream signalling. NompC is a unique ion channel found in Drosophila Melanogaster, which serves as the only known model of the tethered mechanosensitive ion channels. The Cryo-EM structure of NompC was obtained in 2017, but its detailed gating mechanism is yet to know. In this project, we plan to perform extensive molecular dynamics simulations to systematically investigate the conformational changes of NompC in the presence of various mechanical forces, thus to reveal which types of forces can lead to the opening of the channel. We will also study the mechanical properties of the ankyrin repeat region, which may act as a spring during the gating process. The Young's modulus, shear modulus, torsion constant and force transfer velocity will be calculated by all-atom molecular dynamics simulations. We expect that a new mechano-gating mechanism of ion channels will be revealed in this project, which can help people to further understand the mechano-sensation of living organisms.