Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmund J. Safra Campus Givat-Ram, 91904, Jerusalem, Israel.
Eur Biophys J. 2010 Jun;39(7):1043-9. doi: 10.1007/s00249-009-0434-0. Epub 2009 Apr 3.
The pH activated M2 H(+) channel from influenza A has been a subject of numerous studies due to following: (1) It serves as a target for the aminoadamantane drugs that block its channel activity. (2) M2's small size makes it amenable to biophysical scrutiny. (3) A single histidine residue is thought to control the pH gating of the channel. Recent FTIR analysis proposed that the helices of the channel rotate about their directors during pH activation. Herein, we report on molecular dynamics simulations of the X-ray structure of the protein with three charged histidine residues, representing the open form of the protein and two rotated forms with neutral histidines, representing its closed form. We compare the channel stability, convergence, interaction with water and hydration of the histidine residues that have been implicated in channel gating. Taken together, we show that both forms of the protein are stable during the course of the MD simulation and that indeed a rotation of the helices leads to channel closure. Finally, we propose a mechanism for channel gating that involves protonation of the histidine residues that necessities their increased solvation.
由于以下原因，流感 A 的 pH 激活 M2 H(+)通道一直是众多研究的主题：(1) 它是阻断其通道活性的氨基金刚烷类药物的靶标。(2) M2 的小尺寸使其易于进行生物物理研究。(3) 一个组氨酸残基被认为控制着通道的 pH 门控。最近的 FTIR 分析提出，通道的螺旋在 pH 激活过程中围绕其轴旋转。在此，我们报告了带有三个带电组氨酸残基的蛋白质的 X 射线结构的分子动力学模拟，代表蛋白质的开放形式和两个带有中性组氨酸的旋转形式，代表其闭合形式。我们比较了与通道门控相关的组氨酸残基的通道稳定性、收敛性、与水的相互作用和水合作用。总之，我们表明在 MD 模拟过程中两种蛋白质形式都是稳定的，并且实际上螺旋的旋转导致通道关闭。最后，我们提出了一种涉及组氨酸残基质子化的通道门控机制，这需要增加其溶剂化。
