Molecular dynamics calculations suggest a conduction mechanism for the M2 proton channel from influenza A virus
Molecular dynamics calculations suggest a conduction mechanism for the M2 proton channel from influenza A virus
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DOI：
10.1073/pnas.0811720106
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发表时间：
2009-01-27
影响因子：
11.1
通讯作者：
Klein, Michael L.
中科院分区：
文献类型：
--
作者：
Khurana, Ekta;Dal Peraro, Matteo;Klein, Michael L.
甲型流感病毒的M2蛋白被低内体pH激活，并执行质子转移到病毒内部的基本功能。病毒粒子内pH值的降低对于病毒遗传物质的脱壳和进一步复制至关重要。M2同源四聚体束的跨膜区的X射线晶体[Stouffer AL，et al.（2008）Nature 451：596-599]和溶液NMR [Schnell JR，Chou JJ（2008）Nature 451：591-595]结构都揭示了在一端具有窄收缩的孔，留下了关于质子如何进入通道的问题。His-37是质子化和质子选择性传导所必需的，位于晶体学和NMR结构的孔隙中。在这里，我们探讨了不同的质子化状态的M2束在一个双层的His-37残基使用分子动力学（MD）模拟。当His-37残基为中性时，蛋白质偏好开放（外）-封闭（内）构象，其中通道对病毒外部环境开放，但对病毒内部环境封闭。质子从病毒外部扩散到通道中以及四聚体中His-37残基的质子化稳定了相反门控的闭合（出）-开放（入）构象。因此，质子可能通过转运蛋白样机制进行，其中蛋白质在开放（出）-封闭（入）和封闭（出）-开放（入）构象之间交替，并且His-37在每次转换期间被质子化/去质子化。类似转运体的机制与M2束的已知性质一致，包括其相对较低的质子通量率和较强的整流行为。
The M2 protein of the influenza A virus is activated by low endosomal pH and performs the essential function of proton transfer into the viral interior. The resulting decrease in pH within the virion is essential for the uncoating and further replication of the viral genetic material. The x-ray crystal [Stouffer AL, et al. ( 2008) Nature 451: 596-599] and solution NMR [Schnell JR, Chou JJ ( 2008) Nature 451: 591-595] structures of the transmembrane region of the M2 homo-tetrameric bundle both revealed pores with narrow constrictions at one end, leaving a question as to how protons enter the channel. His-37, which is essential for protongating and selective conduction of protons, lies in the pore of the crystallographic and NMR structures. Here, we explore the different protonation states of the His-37 residues of the M2 bundle in a bilayer using molecular dynamics ( MD) simulations. When the His-37 residues are neutral, the protein prefers an Open(out)-Closed(in) conformation in which the channel is open to the environment on the outside of the virus but closed to the interior environment of the virus. Diffusion of protons into the channel from the outside of the virus and protonation of His-37 residues in the tetramer stabilizes an oppositely gated Closed(out)-Open(in) conformation. Thus, protons might be conducted through a transporter-like mechanism, in which the protein alternates between Open(out)-Closed(in) and Closed(out)-Open(in) conformations, and His-37 is protonated/deprotonated during each turnover. The transporter-like mechanism is consistent with the known properties of the M2 bundle, including its relatively low rate of proton flux and its strong rectifying behavior.