Gating motions in voltage-gated potassium channels revealed by coarse-grained molecular dynamics simulations
Gating motions in voltage-gated potassium channels revealed by coarse-grained molecular dynamics simulations
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DOI：
10.1021/jp709675e
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发表时间：
2008-03-20
影响因子：
3.3
通讯作者：
Tarek, Mounir
中科院分区：
文献类型：
--
作者：
Treptow, Werner;Marrink, Siewert-J;Tarek, Mounir
电压门控钾离子通道是一种广泛存在的跨膜蛋白，参与兴奋性组织的电信号传导。这些通道的基本特性是响应于膜电位的变化而打开或关闭的能力。迄今为止，它们基于结构的激活机制仍不清楚，并且关于这些门在分子水平上如何起作用存在很大的争议，特别是电压传感器域的运动如何耦合到通道门控。到目前为止，所有提出的这种耦合的机制是基于开放的电压门控Kv1.2通道的晶体结构和基于电生理学实验的封闭形式的结构模型。在这里，我们使用粗粒（CG）的分子动力学模拟，允许构象变化从开放到封闭形式的通道（嵌入在其膜环境）进行跟踪。尽管低特异性的CG力场，得到的封闭结构满足几个实验的限制。总体结果表明了门控机制，其中S4-S5接头的侧向位移导致门的关闭。仅注意到S4螺旋的小的上下移动。此外，该研究表明通道的细胞内四聚化结构域的一种特殊的向上运动，因此提供了关于该结构域如何进一步调节Kv通道传导的分子观点。
Voltage-gated potassium (Kv) channels are ubiquitous transmembrane proteins involved in electric signaling of excitable tissues. A fundamental property of these channels is the ability to open or close in response to changes in the membrane potential. To date, their structure-based activation mechanism remains unclear, and there is a large controversy on how these gates function at the molecular level, in particular, how movements of the voltage sensor domain are coupled to channel gating. So far, all mechanisms proposed for this coupling are based on the crystal structure of the open voltage-gated Kv1.2 channel and structural models of the closed form based on electrophysiology experiments. Here, we use coarse-grain (CG) molecular dynamics simulations that allow conformational changes from the open to the closed form of the channel (embedded in its membrane environment) to be followed. Despite the low specificity of the CG force field, the obtained closed structure satisfies several experimental constraints. The overall results suggest a gating mechanism in which a lateral displacement the S4-S5 linker leads to a closing of the gate. Only a small up-down movement of the S4 helices is noticed. Additionally, the study suggests a peculiar upward motion of the intracellular tetramerization domain of the channel, hence providing a molecular view on how this domain may further regulate conduction in Kv channels.