A Novel Approach to Simulating the Gating Transitions of Mechanosensitive Channels.
A Novel Approach to Simulating the Gating Transitions of Mechanosensitive Channels.
复制标题
模拟机械敏感通道门控转换的新方法。
DOI：
10.1016/j.bpj.2020.12.004
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发表时间：
2021
影响因子：
3.4
通讯作者：
Gumbart,JamesC
中科院分区：
文献类型：
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作者：
Gumbart,JamesC
长期以来，膜一直被认为对细胞起着多种关键作用，包括充当屏障和守门人，控制细胞与外部环境之间的物质和信息流动。最近，人们已经意识到，膜也作为传感器，响应机械刺激，通过调制的行为越来越多的确定膜嵌入蛋白质在所有领域的生活。这些蛋白质中最主要的是所谓的机械敏感（MS）离子通道，其中一些可以在膜张力变化下打开。MS通道的存在首先在听觉毛细胞（1）和鸡胚骨骼肌（2）中被发现。后来在细菌中也发现了它们（3），它们使这些生物体能够避免在膨压突然增加的情况下破裂，这种情况可能发生在降雨期间，通过快速（在几毫秒内）从细胞中释放渗透剂（4）。MS通道的最初几种结构是在20世纪90年代末和21世纪初确定的，即大电导（MscL）和小电导（MscS）的机械敏感通道（图1）。分子动力学（MD）模拟很快就由许多小组进行，试图了解通道如何受到张力的影响，特别是寻找关闭和打开状态之间的门控转换（5-8）。诱导向开放状态转变的最常见的计算方法是直接向蛋白质施加外力（6，9）或向膜施加张力（5，10）。然而，由于模拟时间尺度（ns）通常小于门控时间尺度（ms-ms），因此需要较大的力或张力，从而使蛋白质的构象变化易于解释。
Membranes have long been known to serve multiple critical roles for cells, including acting as barriers and also as gatekeepers, controlling the flow of materials and information between the cell and the exterior environment. More recently, it has been realized that membranes also act as sensors, responding to mechanical stimuli through modulation of the behavior of a growing number of identified membrane-embedded proteins in all domains of life. Chief among these proteins are so-called mechanosensitive (MS) ion channels, some of which can open under a change in membrane tension. The existence of MS channels was first recognized in auditory hair cells (1) and in embryonic chick skeletal muscle (2). They were later discovered in bacteria as well (3), where they allow these organisms to avoid bursting under the sudden increases in turgor pressure that might occur during, eg, rainfall by rapidly (within milliseconds) releasing osmolytes from the cell (4). The first few structures of MS channels were determined in the late 1990s and early 2000s, namely the mechanosensitive channel of large conductance (MscL) and small conductance (MscS)(Fig. 1). Molecular dynamics (MD) simulations were soon after carried out by a number of groups in an attempt to understand how the channels are affected by application of tension, looking particularly for the gating transitions between closed and open states (5–8). The most common computational approach to induce a transition to the open state has been the direct application of external forces to the protein (6, 9) or of tension to the membrane (5, 10). However, because the simulation timescale (ns) was typically less than the timescale of gating (ms–ms), large forces or tensions were required, making the resulting conformational changes of the proteins open to interpretation.