Jorgensen Christian, Furini Simone, Domene Carmen
Department of Chemistry, King's College London, London, United Kingdom.
Department of Medical Biotechnologies, University of Siena, Siena, Italy.
Biophys J. 2016 Sep 20;111(6):1214-1222. doi: 10.1016/j.bpj.2016.08.009.
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 ∼3.6 μs 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 I679 and E684.
离子通道能使离子顺着生理电化学梯度进行扩散。离子通透的调节对于细胞的生理功能至关重要，而离子通道的调节异常与众多的通道病相关。瞬时受体电位（TRP）离子通道家族中的离子通透机制目前在原子水平上尚不清楚。在这项工作中，我们采用了一种离子通透模拟策略（带偏差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香草酸受体1（TRPV1）离子通道中单价（Na⁺、K⁺）离子的通透情况。通过约3.6微秒的模拟轨迹，我们获得了TRPV1非选择性本质的原子证据。我们的分析表明，溶剂化单价离子通过双位点机制以相当的能量势垒穿过选择性过滤器。最后，我们证实了一个细胞内结合位点位于细胞内门控残基I679和E684之间。
