Conformational Activation of a Transmembrane Proton Channel from Constant pH Molecular Dynamics.
Conformational Activation of a Transmembrane Proton Channel from Constant pH Molecular Dynamics.
复制标题
DOI：
10.1021/acs.jpclett.6b01853
复制
发表时间：
2016-10-06
期刊：
影响因子：
--
通讯作者：
Shen J
中科院分区：
文献类型：
--
作者：
Chen W;Huang Y;Shen J
质子偶联跨膜蛋白在人类健康和疾病中起着重要作用，然而，详细的机制往往是难以捉摸的。实验解决质子的位置和结构的细节是具有挑战性的，和传统的分子动力学模拟进行预分配和固定的质子化状态。为了解决这一挑战，在这里，我们说明了使用国家的最先进的连续恒定pH分子动力学（CpHMD），以直接描述流感病毒的M2通道的激活，其中丰富的实验数据是可用的。从封闭的晶体结构开始，模拟揭示了一个pH依赖性的构象转换到一个类似于开放的晶体结构的激活状态。重要的是，模拟提供了与组氨酸四联体滴定偶联的通道开放的自由能，从而提供了M2活化的热力学机制，这与NMR数据一致，并解决了在不同pH下获得的晶体结构的争议。这项工作说明了CpHMD在提供质子-偶联的跨膜通道和转运蛋白。
Proton-coupled transmembrane proteins play important roles in human health and diseases; however, detailed mechanisms are often elusive. Experimentally resolving proton positions and structural details is challenging, and conventional molecular dynamics simulations are performed with preassigned and fixed protonation states. To address this challenge, here we illustrate the use of the state-of-the-art continuous constant pH molecular dynamics (CpHMD) to directly describe the activation of the M2 channel of influenza virus, for which abundant experimental data are available. Starting from the closed crystal structure, simulation reveals a pH-dependent conformational switch to an activated state which resembles the open crystal structure. Importantly, simulation affords the free energy of channel opening coupled to the titration of a histidine tetrad, thereby providing a thermodynamic mechanism for M2 activation, which is consistent with NMR data and resolves the controversy with crystal structures obtained at different pH. This work illustrates the utility of CpHMD in offering previously unattainable conformational details and thermodynamic information for proton-coupled transmembrane channels and transporters.
登录
查看更多内容
影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
影响因子：
3.4
作者：
Chen, Hanning;Wu, Yujie;Voth, Gregory A.
通讯作者：
Voth, Gregory A.
影响因子：
4.8
作者：
Tang, YJ;Zaitseva, F;Pinto, LH
通讯作者：
Pinto, LH
DOI：
10.1073/pnas.1518493112
发表时间：
2015-11-17
影响因子：
11.1
作者：
Thomaston, Jessica L.;Alfonso-Prieto, Mercedes;DeGrado, William F.
通讯作者：
DeGrado, William F.
DOI：
10.1073/pnas.0811720106
发表时间：
2009-01-27
影响因子：
11.1
作者：
Khurana, Ekta;Dal Peraro, Matteo;Klein, Michael L.
通讯作者：
Klein, Michael L.