Domain and interdomain energetics underlying gating in Shaker-type Kv channels.
Domain and interdomain energetics underlying gating in Shaker-type Kv channels.
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DOI：
10.1016/j.bpj.2014.08.015
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发表时间：
2014-10
影响因子：
3.4
通讯作者：
A. Peyser;D. Gillespie;R. Roth;W. Nonner
中科院分区：
文献类型：
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作者：
A. Peyser;D. Gillespie;R. Roth;W. Nonner
为了理解门控事件的时间基许多数量级慢于电压门控离子通道，如theShaker型KV通道的原子运动，多尺度物理模型构建从实验上表征的电压传感器（VS）域耦合到疏水门。四个VS域描述的电压钳条件下的连续静电模型，由门域的离子流的控制描述的汽锁机制，和简单的耦合原理是由已知的实验结果和试错通知。为每个元素计算的配置能量用于产生总哈密顿量，该总哈密顿量是施加电压、VS位置和栅极半径的函数。我们计算宏观实验室观测的物理力学期望值。这种方法与分子动力学模型形成鲜明对比，分子动力学模型受到越来越大的规模的挑战，动力学模型假设概率分布，而不是从基础物理学中推导出来。这个通用的模型预测以及theShakercharge/电压和电导/电压的关系，这些结果的严格约束，使我们能够定量评估潜在的物理机制。由VS域拾取的总电功比驱动门本身所需的功大一个数量级，这表明电压门控机制的进化灵活性有一个充满活力的基础。由VS-门耦合关系描述的VS域的合作滑动和互锁行为导致实验观察到的双门。这种工程方法应证明是有用的调查的各种元素的门控特性和退化的行为，由于突变。
To understand gating events with a time-base many orders-of-magnitude slower than that of atomic motion in voltage-gated ion channels such as theShaker-type KVchannels, a multiscale physical model is constructed from the experimentally well-characterized voltage-sensor (VS) domains coupled to a hydrophobic gate. The four VS domains are described by a continuum electrostatic model under voltage-clamp conditions, the control of ion flow by the gate domain is described by a vapor-lock mechanism, and the simple coupling principle is informed by known experimental results and trial-and-error. The configurational energy computed for each element is used to produce a total Hamiltonian that is a function of applied voltage, VS positions, and gate radius. We compute statistical-mechanical expectation values of macroscopic laboratory observables. This approach stands in contrast with molecular-dynamic models which are challenged by increasing scale, and kinetic models which assume a probability distribution rather than derive it from the underlying physics. This generic model predicts well theShakercharge/voltage and conductance/voltage relations; the tight constraints underlying these results allow us to quantitatively assess the underlying physical mechanisms. The total electrical work picked up by the VS domains is an order-of-magnitude larger than the work required to actuate the gate itself, suggesting an energetic basis for the evolutionary flexibility of the voltage-gating mechanism. The cooperative slide-and-interlock behavior of the VS domains described by the VS-gate coupling relation leads to the experimentally observed bistable gating. This engineering approach should prove useful in the investigation of various elements underlying gating characteristics and degraded behavior due to mutation.