Dynamics, Energetics, and Selectivity of the Low-K+ KcsA Channel Structure
Dynamics, Energetics, and Selectivity of the Low-K+ KcsA Channel Structure
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DOI：
10.1016/j.jmb.2009.04.038
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发表时间：
2009-06-12
影响因子：
5.6
通讯作者：
Furini, Simone
中科院分区：
文献类型：
--
作者：
Domene, Carmen;Furini, Simone
钾通道是一个多样化的整合膜蛋白家族，K+ 可以选择性地通过它。关于与钾通道的打开/关闭和导电/非导电状态相关的构象变化的性质，目前存在争论。这些通道通过一种称为 C 型失活的机制改变其电导来部分发挥其功能。 K+ 通道激活后不久，其选择性过滤器就会停止以取决于各种刺激的速率传导离子。 C型失活的分子机制尚未完全清楚。然而，在低 K+ 浓度存在下获得的 KcsA 通道的 X 射线结构被认为代表了处于 C 型失活状态的 K+ 通道。在这里，对显式脂质双层中的低 K+ KcsA 结构进行了广泛的、完全原子分子动力学和自由能模拟，以评估该结构的稳定性及其结合位点的选择性。我们发现低 K+ KcsA 结构在分子动力学模拟的时间尺度上是稳定的，并且离子优选保留在 S1 和 S4 中。在没有离子的情况下，选择性滤波器向不对称结构演化，正如在 KcsA 和 KirBac 高 K+ 结构的其他计算中观察到的那样。低K+ KcsA结构不能被Na+、K+或Rb+渗透，并且其结合位点的选择性与高K+结构不同。 (C) 2009 Elsevier Ltd. 保留所有权利。
Potassium channels are a diverse family of integral membrane proteins through which K+ can pass selectively. There is ongoing debate about the nature of conformational changes associated with the opening/closing and conductive/nonconductive states of potassium channels. The channels partly exert their function by varying their conductance through a mechanism known as C-type inactivation. Shortly after the activation of K+ channels, their selectivity filter stops conducting ions at a rate that depends on various stimuli. The molecular mechanism of C-type inactivation has not been fully understood yet. However, the X-ray structure of the KcsA channel obtained in the presence of low K+ concentration is thought to be representative of a K+ channel in the C-type inactivated state. Here, extensive, fully atomistic molecular dynamics and free-energy simulations of the low-K+ KcsA structure in an explicit lipid bilayer are performed to evaluate the stability of this structure and the selectivity of its binding sites. We find that the low-K+ KcsA structure is stable on the timescale of the molecular dynamics simulations performed, and that ions preferably remain in S1 and S4. In the absence of ions, the selectivity filter evolves toward an asymmetric architecture, as already observed in other computations of the high-K+ structure of KcsA and KirBac. The low-K+ KcsA structure is not permeable by Na+, K+, or Rb+, and the selectivity of its binding sites is different from that of the high-K+ structure. (C) 2009 Elsevier Ltd. All rights reserved.