Mapping the Gating and Permeation Pathways in the Voltage-Gated Proton Channel Hv1
Mapping the Gating and Permeation Pathways in the Voltage-Gated Proton Channel Hv1
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DOI：
10.1016/j.jmb.2014.11.018
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发表时间：
2015-01-16
影响因子：
5.6
通讯作者：
Larsson, H. Peter
中科院分区：
文献类型：
--
作者：
Chamberlin, Adam;Qiu, Feng;Larsson, H. Peter
电压门控质子通道(Hv1)广泛存在于自然界，参与多种生理过程。然而，Hv1的编码基因直到2006年才被发现。该通道缺乏足够的结构信息，阻碍了对通道激活和质子渗透的分子机制的理解。本研究采用模拟与实验相结合的方法，进一步发展现有的Hv1通道模型。我们的研究提供了对通道门控和质子渗透途径的特征的洞察。我们将以前开发的开态和闭态结构与最近的晶体结构进行比较，后者假设通道处于关闭状态。使用全原子分子动力学模拟和一系列轨迹的组合，以及用于广泛的过渡路径采样和进化的弦方法，提供了对门控路径的见解。研究了详细的残基相互作用分布和水化分布，以绘制该通道中的门控路径。特别是，它使我们能够识别潜在的中间态，并将它们与Takeshita等人实验观察到的晶体结构进行比较。(Takeshita K，Sakata S，Yamashita E，Fujiwara Y，Kawanabe A，Kurokawa T，等.电压门控质子通道的X射线晶体结构。《自然》2014)。通过电生理记录和自由能模拟相结合的方法，研究了野生型和突变型Hv1通道中离子传输的机制。有了这些结果，我们能够进一步完善关于选择性过滤器的位置和功能的想法。改进的结构模型将是未来对这一通道的研究和开发针对细胞质子运输的新药所必需的。(C)2014爱思唯尔有限公司。保留所有权利。
Voltage-gated proton channels (Hv1) are ubiquitous throughout nature and are implicated in numerous physiological processes. The gene encoding for Hv1, however, was only identified in 2006. The lack of sufficient structural information of this channel has hampered the understanding of the molecular mechanism of channel activation and proton permeation. This study uses both simulation and experimental approaches to further develop existing models of the Hv1 channel. Our study provides insights into features of channel gating and proton permeation pathway. We compare open- and closed-state structures developed previously with a recent crystal structure that traps the channel in a presumably closed state. Insights into gating pathways were provided using a combination of all-atom molecular dynamics simulations with a swarm of trajectories with the string method for extensive transition path sampling and evolution. A detailed residue residue interaction profile and a hydration profile were studied to map the gating pathway in this channel. In particular, it allows us to identify potential intermediate states and compare them to the experimentally observed crystal structure of Takeshita et al. (Takeshita K, Sakata S, Yamashita E, Fujiwara Y, Kawanabe A, Kurokawa T, et al. X-ray crystal structure of voltage-gated proton channel. Nature 2014). The mechanisms governing ion transport in the wild-type and mutant Hv1 channels were studied by a combination of electrophysiological recordings and free energy simulations. With these results, we were able to further refine ideas about the location and function of the selectivity filter. The refined structural models will be essential for future investigations of this channel and the development of new drugs targeting cellular proton transport. (C) 2014 Elsevier Ltd. All rights reserved.