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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular Dynamics Calculations Suggest A Conduction Mechanism For The M2 Proton Channel From Influenza A Virus
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Molecular Dynamics Calculations Suggest A Conduction Mechanism For The M2 Proton Channel From Influenza A Virus

机译：分子动力学计算表明甲型流感病毒M2质子通道的传导机制

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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 proton-gating 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 pro-tonated/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.
机译：较低的内体pH值可激活A型流感病毒的M2蛋白，并执行质子转移到病毒内部的基本功能。病毒体中pH的最终降低对于病毒基因材料的脱膜和进一步复制至关重要。 X射线晶体[Stouffer AL等。 （2008）Nature 451：596-599]和溶液NMR [Schnell JR，Chou JJ（2008）Nature 451：591-595] M2同四聚体束的跨膜区域的结构均显示出在一端具有狭窄收缩的孔。 ，就质子如何进入通道提出了疑问。 His-37对质子门控和质子的选择性传导至关重要，位于晶体学和NMR结构的孔中。在这里，我们使用分子动力学（MD）模拟探索双层中M2束的His-37残基的不同质子化状态。当His-37残基为中性时，该蛋白偏向于Open_（out）-Closed_（in）构象，在该构象中，通道对病毒外部的环境开放，但对病毒的内部环境开放。质子从病毒外部扩散到通道中，四聚体中His-37残基的质子化稳定了相反门控的Closed_（out）-Open_（in）构象。因此，质子可能通过转运蛋白样机制进行传导，其中蛋白质在Open_（out）-Closed_（in）和Closed_（out）-Open_（in）构象之间交替，His-37被质子化/去质子化在每次营业期间。类似转运蛋白的机制与M2束的已知特性是一致的，包括其相对较低的质子通量率和强大的整流性能。

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