Exploring models of the influenza A M2 channel: MD simulations in a phospholipid bilayer
Exploring models of the influenza A M2 channel: MD simulations in a phospholipid bilayer
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DOI：
10.1016/s0006-3495(00)76572-6
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发表时间：
2000-01-01
影响因子：
3.4
通讯作者：
Sansom, MSP
中科院分区：
文献类型：
--
作者：
Forrest, LR;Kukol, A;Sansom, MSP
甲型流感病毒的M2蛋白形成同源四聚体螺旋束，其充当质子选择性通道。蛋白质的天然形式是97个残基长，尽管代表跨膜部分的肽显示离子通道活性，其（像天然通道）被抗病毒药物金刚烷胺阻断。作为一个小的离子通道，M2可以提供有用的见解更复杂的通道系统。模型的四聚体束的螺旋含有18或22个残基已被模拟，而嵌入在一个完全水合的1-棕榈酰-2-油酰-sn-甘油-3-磷脂酰胆碱双层。已经使用了几种不同的启动模型。这些表明，模拟结果，至少在纳秒的时间尺度上，是敏感的确切的起始结构。在通道的N-末端口的四个可电离天冬氨酸残基的环上进行的静电计算表明，在任何一个时间，只有一个将处于带电状态。阻碍束模型在模拟的持续时间内大多是稳定的，它们的螺旋相对于双层正常保持倾斜。M2螺旋束形成经历呼吸运动的封闭通道，在四聚体和二聚体的二聚体结构之间交替。在这些条件下，要么通道形成一个被困的沃茨袋，要么它包含一个主要在孔隙的C-末端口处破裂的沃茨。这些沃茨在孔中表现出受限的运动，并且以类似于先前模拟由合成亮氨酸-丝氨酸肽的四螺旋束形成的质子通道中所看到的方式有效地“冻结”。
The M2 protein of influenza A virus forms homotetrameric helix bundles, which function as proton-selective channels. The native form of the protein is 97 residues long, although peptides representing the transmembrane section display ion channel activity, which (like the native channel) is blocked by the antiviral drug amantadine. As a small ion channel, M2 may provide useful insights into more complex channel systems. Models of tetrameric bundles of helices containing either 18 or 22 residues have been simulated while embedded in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphatidylcholine bilayer. Several different starting models have been used. These suggest that the simulation results, at least on a nanosecond time scale, are sensitive to the exact starting structure. Electrostatics calculations carried out on a ring of four ionizable aspartate residues at the N-terminal mouth of the channel suggest that at any one time, only one will be in a charged state. Helix bundle models were mostly stable over the duration of the simulation, and their helices remained tilted relative to the bilayer normal. The M2 helix bundles form closed channels that undergo breathing motions, alternating between a tetramer and a dimer-of-dimers structure. Under these conditions either the channel forms a pocket of trapped waters or it contains a column of waters broken predominantly at the C-terminal mouth of the pore. These waters exhibit restricted motion in the pore and are effectively "frozen" in a way similar to those seen in previous simulations of a proton channel formed by a four-helix bundle of a synthetic leucine-serine peptide.