Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel.
Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel.
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DOI：
10.1371/journal.pcbi.1000289
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发表时间：
2009-02
影响因子：
4.3
通讯作者：
Lindahl, Erik
中科院分区：
文献类型：
--
作者：
Bjelkmar, Par;Niemela, Perttu S.;Vattulainen, Ilpo;Lindahl, Erik
电压门控离子通道的结构和动力学，特别是S4螺旋的运动，是当前膜蛋白研究中一个非常有趣和激烈争论的话题。它对膜蛋白的插入和稳定以及发现膜蛋白中的转换如何发生具有重要意义，更不用说在药物设计中的许多应用了。在这里，我们提出了一个完整的1 µs原子细节分子动力学模拟的积分Kv1.2离子通道，包括120，000个原子。通过施加0.052 V/nm的超极化，我们观察到结构重排，包括S4段高达120°的旋转，氢键模式的变化，但只有少量的平移。所有S4节段的细胞外端的较小旋转（± 35°）也存在于没有施加场的参考0.5 µs模拟中，这表明晶体结构可能与电压传感器的自然状态略有不同。超极化后的构象变化与S4中310螺旋含量的增加密切相关，从细胞内侧开始。这可以支持从晶体结构过渡的模型，其中超极化使S4-脂质氢键不稳定，这导致螺旋旋转以保持精氨酸侧链远离疏水相，并且通过向下平移的最终松弛的驱动力是部分熵的，这可以解释缓慢的过程。在整个模拟的后半部分（0.5-1 µs），模拟通道的跨膜部分的坐标实际上比起始结构更接近最近确定的更高分辨率的Kv1.2嵌合体通道。再加上在实验中观察到的匹配位置的脂质结合和膜的显着变薄，这为微秒级膜蛋白模拟的预测能力提供了额外的支持。跨细胞膜运输离子的蛋白质是细胞生命所必需的。传导带正电荷的钾离子的蛋白质是心跳和神经冲动产生的关键参与者，因为它们调节细胞的电兴奋性（与转运其他离子的蛋白质一起）。这些特殊的离子通道响应细胞膜上的电压变化而打开和关闭，但这一过程的细节仍然没有完全了解。然而，已知的主要蛋白质元件是含有几个电荷的螺旋部分。通过新的计算机模拟方法，我们已经能够对嵌入在一片膜中的整个钾通道进行前所未有的长时间原子模拟，以帮助揭示这种门控过程。在改变跨膜电压时，我们观察到该螺旋蛋白片段的结构变化，这似乎是通道从开放状态转变为闭合状态的早期迹象。这在以前也被认为是浇口工艺的关键。在原子水平上理解这些结构变化对于推进基础科学和实现针对电压调节离子通道的药物设计至关重要。
Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins—not to mention numerous applications in drug design. Here, we present a full 1 µs atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120° rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation (∼35°) of the extracellular end of all S4 segments is present also in a reference 0.5 µs simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 310 helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4–lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5–1 µs). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations. Proteins that transport ions across the cellular membrane are essential for cellular life. The proteins conducting positively charged potassium ions are key players in heart beat and nerve impulse generation because they are regulating the electrical excitability of the cell (together with proteins transporting other ions). These particular ion channels open and close in response to voltage changes across cellular membranes, but the details of this process are still not fully understood. It is, however, known that the main protein element responsible is a helical section containing several charges. Through new computer simulation methods, we have been able to run unprecedentedly long atomic simulations of an entire potassium channel embedded within a patch of membrane to help to shed new light on this gating process. Upon changing the voltage across the membrane, we observe a change in structure of this helical protein segment that appears to be an early sign of transition from the open to the closed state of the channel. This has also been previously proposed to be critical for the gating process. Understanding these structural changes on an atomic level is essential for both advancing basic science and enabling drug design targeting of voltage-regulated ion channels.
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影响因子：
16.2
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