A unique activation-promotion mechanism of the influenza B M2 proton channel uncovered by multiscale simulations
A unique activation-promotion mechanism of the influenza B M2 proton channel uncovered by multiscale simulations
复制标题
多尺度模拟揭示乙型流感M2质子通道独特的激活促进机制
DOI：
10.1039/c9cp00130a
复制
发表时间：
2019
影响因子：
3.3
通讯作者：
Zheng Qingchuan
中科院分区：
文献类型：
--
作者：
Zhang Yulai;Zhang Hongxing;Zheng Qingchuan
流感B型M2蛋白（BM2）形成一个酸激活的质子通道，这对病毒的生命周期很重要。尽管进行了大量的研究，但BM2质子通道的详细激活机制往往是难以捉摸的。本文采用多尺度计算机模拟，包括经典分子动力学、恒定pH分子动力学（CpHMD）和量子力学/分子力学（QM/MM）方法，系统表征了BM2TM结构域的pH调控机制。我们的模拟揭示了从c端闭合到c端开放构象的ph依赖的构象转换，并提供了与His19四分体滴定耦合的构象激活的自由能。重要的是，我们的结果证实了His19四元体和His27四元体之间的耦合滴定，并确定了低pH下全阳离子态（His2744+）占主导地位（His19四元体在+2、+3和+4电荷态）。我们的QM/MM模拟表明，第二种可滴定组氨酸His27可以进一步促进BM2的酸活化，加速质子与HxxxW基序的解离，从而促进BM2的质子传导。综上所述，本文提出了一种独特的BM2质子通道的“活化-促进机制”，这些结果可能有助于对其他类似质子通道的理解和BM2抑制剂的开发。
The influenza B M2 protein (BM2) forms an acid-activated proton channel that is important for the virus's lifecycle. Despite extensive research efforts, the detailed activation mechanism of the BM2 proton channel is often elusive. Herein a pH-regulated mechanism of the BM2TM domain has been systematically characterized using multiscale computer simulations, including classical molecular dynamics, constant pH molecular dynamics (CpHMD) and quantum mechanics/molecular mechanics (QM/MM) approaches. Our simulations reveal a pH-dependent conformational switch from the C-terminal closed to the C-terminal open conformers, and provide the free energy of conformational activation coupled to the titration of the His19 tetrad. Importantly, our results confirm the coupling titration between the His19 tetrad and His27 tetrad, and identify that the full-cationic state (His2744+) dominates at the low pH (the His19 tetrad at +2, +3 and +4 charge states). Our QM/MM simulations indicate that the second titratable histidine, His27, could further promote the BM2 acid activation and speed up proton dissociation from the HxxxW motif, thus facilitating proton conduction by BM2. Taken together, a unique “activation–promotion mechanism” about the BM2 proton channel is proposed, and these results may be helpful for the understanding of other similar proton channels and the development of BM2 inhibitors.