Structural Features and Energetics of the Periplasmic Entrance Opening of the Outer Membrane Channel TolC Revealed by Molecular Dynamics Simulation and Markov State Model Analysis
Structural Features and Energetics of the Periplasmic Entrance Opening of the Outer Membrane Channel TolC Revealed by Molecular Dynamics Simulation and Markov State Model Analysis
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分子动力学模拟和马尔可夫态模型分析揭示外膜通道TolC周质入口开口的结构特征和能量
DOI：
10.1021/acs.jcim.8b00957
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发表时间：
2019-02
影响因子：
5.6
通讯作者：
Wang Wenning
中科院分区：
文献类型：
--
作者：
Weng Jingwei;Wang Wenning
TolC是一种负责底物跨膜转运的通道蛋白，也是革兰氏阴性菌中三方多药外排泵的一部分。TolC的晶体结构表明，在静息状态下，周质入口是紧密关闭的，而底物转运肯定需要入口打开。封闭的周质入口如何打开以允许底物通过仍然是难以捉摸的。在这项工作中，我们构建了一个马尔可夫状态模型，从群的全原子分子动力学（MD）模拟轨迹，它描绘了能量的构象变化的TolC。周质入口的开放导致自由能的单调增加，并伴随着interprotomer相互作用的破坏，而intraprotomer相互作用保持完整。计算了Na ~+和Cl ~-沿通道沿着渗透的多离子平均力势（PMF）分布，由此得到的阳离子/阴离子渗透率比与电生理实验结果吻合较好。这些结果不仅加深了我们对孤立的TolC构象动力学的理解，而且也提供了有价值的愿景，其在三方外排泵的功能状态。
TolC is a channel protein responsible for substrate translocation across the outer membrane, and it is also a part of the tripartite multidrug efflux pumps in Gram-negative bacteria. The crystal structure of TolC shows that the periplasmic entrance is tightly closed in the resting state, while substrate translocation definitely requires the entrance to open. How the occluded periplasmic entrance opens to allow passage of substrates remains elusive. In this work, we constructed a Markov state model from swarms of all-atom molecular dynamics (MD) simulation trajectories, which delineates the energetics of the conformational changes of TolC. Opening of the periplasmic entrance results in a monotonic increase in free energy and is accompanied by disruption of interprotomer interactions, whereas the intraprotomer interactions remain intact. Multi-ion potential of mean force (PMF) profiles for Na+ and Cl- permeation along the channel have been calculated, and the cation/anion permeability ratio derived from which are in good agreement with electrophysiological experiments. These results not only deepen our understanding of conformational dynamics of isolated TolC but also provide valuable vision of its functioning state in tripartite efflux pumps.
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