What are the effects of the serine triad on proton conduction of an influenza B M2 channel? An investigation by molecular dynamics simulations
What are the effects of the serine triad on proton conduction of an influenza B M2 channel? An investigation by molecular dynamics simulations
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丝氨酸三联体对 B 型流感 M2 通道的质子传导有何影响？
DOI：
10.1039/c9cp00612e
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发表时间：
2019
影响因子：
3.3
通讯作者：
Zheng Qing-Chuan
中科院分区：
文献类型：
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作者：
Zhang Yue;Zheng Qing-Chuan
B型流感病毒四聚体M2通道(BM2)是一种酸激活的质子通道，在B型流感病毒的生命周期中具有重要作用。保守的HxxxW基序负责质子传导和通道门控。在这项研究中，为了探索丝氨酸三联体(S9，S12和S16)对质子传导的影响，我们在H19四联体的不同质子化状态下进行了经典分子动力学(CMD)模拟和自适应转向分子动力学(ASMD)模拟。孔半径和C端倾角的结果表明，质子化的H19产生的静电斥力是打开BM2通道的关键驱动力。S16和质子化的H19之间的氢键可以稳定分子的开态。溶剂可及表面积和水密度表明，丝氨酸三元化合物提供的极性亲水环境促进了水线的形成，从而对质子传导产生了有利的影响。突变体研究验证并支持了这些观点。我们的工作阐明了丝氨酸三联体对BM2通道质子传导的影响，这将有助于我们深入了解BM2的质子传导机制，并为抗BM2的抗病毒药物设计提供新的视角。
The tetrameric influenza B M2 channel (BM2), an acid activated proton channel, is important in the influenza virus B lifecycle. A conserved HxxxW motif is responsible for proton conduction and channel gating. In this study, to explore the effects of the serine triad (S9, S12 and S16) on proton conduction, we performed classical molecular dynamics (CMD) simulations and adaptive steered molecular dynamics (ASMD) simulations at different protonation states of the H19 tetrad. The results of the pore radius and the C-terminal tilt angle show that the electrostatic repulsion induced by protonated H19 is the key driving force for opening the BM2 channel. The open states could be stabilized by the hydrogen bonds between S16 and protonated H19. The solvent accessible surface area and water density indicate that the polar hydrophilic environment provided by the serine triad facilitates the formation of a water wire, and then exhibits favourable effects on proton conduction. The mutant research verifies and supports these views. Our work clarifies the effects of the serine triad on proton conduction in the BM2 channel, which would help us deeply understand the proton conduction mechanism in BM2 and provides a new perspective for antiviral drug design against BM2.