Energetics of Ion Permeation in an Open-Activated TRPV1 Channel
Energetics of Ion Permeation in an Open-Activated TRPV1 Channel
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DOI：
10.1016/j.bpj.2016.08.009
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发表时间：
2016-09-20
影响因子：
3.4
通讯作者：
Domene, Carmen
中科院分区：
文献类型：
--
作者：
Jorgensen, Christian;Furini, Simone;Domene, Carmen
离子通道使离子沿生理电化学梯度扩散。离子渗透的调节对细胞的生理功能至关重要，离子通道的错误调节与无数的通道病变有关。暂态受体电位（TRP）离子通道家族中的离子渗透机制目前尚未在原子水平上被理解。在这项工作中，我们采用离子渗透模拟策略（带有偏态交换元动力学的分子动力学模拟）来研究和比较开放激活的TRP vanilids -1 （TRPV1）离子通道中的一价（Na+, K+）离子渗透。使用类似3.6 μ s的模拟轨迹，我们获得了TRPV1非选择性性质的原子证据。我们的分析表明，溶剂化的单价离子通过选择性过滤器，具有相当的能垒，通过两个位点机制渗透。最后，我们证实了细胞内结合位点位于细胞内门残基1679和E684之间。
Ion channels enable diffusion of ions down physiological electrochemical gradients. Modulation of ion permeation is crucial for the physiological functioning of cells, and misregulation of ion channels is linked to a myriad of channelopathies. The ion permeation mechanism in the transient receptor potential (TRP) ion channel family is currently not understood at an atomistic level. In this work, we employed a simulation strategy for ion permeation (molecular-dynamics simulations with bias-exchange metadynamics) to study and compare monovalent (Na+, K+) ion permeation in the open-activated TRP vanniloid-1 (TRPV1) ion channel. Using similar to 3.6 mu s of simulation trajectories, we obtained atomistic evidence for the nonselective nature of TRPV1. Our analysis shows that solvated monovalent ions permeate through the selectivity filter with comparable energetic barriers via a two-site mechanism. Finally, we confirmed that an intracellular binding site is located between the intracellular gate residues 1679 and E684.