Theory and simulation of ion conduction in the pentameric GLIC channel.
Theory and simulation of ion conduction in the pentameric GLIC channel.
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DOI：
10.1021/ct2009279
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发表时间：
2012-10-09
影响因子：
5.5
通讯作者：
Hummer, Gerhard
中科院分区：
文献类型：
--
作者：
Zhu, Fangqiang;Hummer, Gerhard
GLIC是五聚体配体门控离子通道大家族的细菌成员。为了研究通过GLIC和其他膜通道的离子传导，我们结合联合收割机的一维势的平均力的离子通道与Smoluchowski扩散模型，使得有可能计算单通道电导率的制度，从全原子分子动力学（MD）模拟的低离子浓度。然后，我们进行MD模拟研究钠离子传导通过GLIC跨膜孔在两个系统中具有不同的本体离子浓度。平均力的离子势，计算从伞采样模拟与哈密顿副本交换，揭示了一个主要的障碍，在疏水收缩的孔。这种障碍的离子传输的相关性被证实的提交功能，在障碍区域急剧上升。从自由演化的Na+离子开始在势垒顶部，我们估计的有效扩散系数在势垒区域，并随后计算的孔隙的电导。所得的扩散率比较以及与位置相关的离子扩散系数从约束模拟。从扩散模型得到的离子电导同意通过反应通量率计算确定的值。我们的研究结果表明，GLIC晶体结构中的构象，在140 mM离子浓度下的电导估计为~1皮西门子，与通道的生理开放状态一致。
GLIC is a bacterial member of the large family of pentameric ligand-gated ion channels. To study ion conduction through GLIC and other membrane channels, we combine the one-dimensional potential of mean force for ion passage with a Smoluchowski diffusion model, making it possible to calculate single-channel conductance in the regime of low ion concentrations from all-atom molecular dynamics (MD) simulations. We then perform MD simulations to examine sodium ion conduction through the GLIC transmembrane pore in two systems with different bulk ion concentrations. The ion potentials of mean force, calculated from umbrella sampling simulations with Hamiltonian replica exchange, reveal a major barrier at the hydrophobic constriction of the pore. The relevance of this barrier for ion transport is confirmed by a committor function that rises sharply in the barrier region. From the free evolution of Na+ ions starting at the barrier top, we estimate the effective diffusion coefficient in the barrier region, and subsequently calculate the conductance of the pore. The resulting diffusivity compares well with the position-dependent ion diffusion coefficient obtained from restrained simulations. The ion conductance obtained from the diffusion model agrees with the value determined via a reactive-flux rate calculation. Our results show that the conformation in the GLIC crystal structure, with an estimated conductance of ~1 picosiemens at 140 mM ion concentration, is consistent with a physiologically open state of the channel.
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