Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA.
Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19814-9. doi: 10.1073/pnas.1009313107. Epub 2010 Nov 1.
Nerve signaling in humans and chemical sensing in bacteria both rely on the controlled opening and closing of the ion-conducting pore in pentameric ligand-gated ion channels. With the help of a multiscale simulation approach that combines mixed elastic network model calculations with molecular dynamics simulations, we study the opening and closing of the pore in Gloeobacter violaceus channel GLIC at atomic resolution. In our simulations of the GLIC transmembrane domain, we first verify that the two endpoints of the transition are open and closed to sodium ion conduction, respectively. We then show that a two-stage tilting of the pore-lining helices induces cooperative drying and iris-like closing of the channel pore. From the free energy profile of the gating transition and from unrestrained simulations, we conclude that the pore of the isolated GLIC transmembrane domain closes spontaneously. The mechanical work of opening the pore is performed primarily on the M2-M3 loop. Strong interactions of this short and conserved loop with the extracellular domain are therefore crucial to couple ligand binding to channel opening.
人类的神经信号传递和细菌的化学感应都依赖于五聚体配体门控离子通道中离子传导孔的受控开启和关闭。借助一种结合了混合弹性网络模型计算和分子动力学模拟的多尺度模拟方法，我们以原子分辨率研究了 Gloeobacter violaceus 通道 GLIC 中孔的开启和关闭。在我们对 GLIC 跨膜结构域的模拟中，我们首先验证了两个转折点分别对钠离子传导开放和关闭。然后我们表明，孔衬螺旋的两阶段倾斜诱导了通道孔的协同干燥和鸢尾花样关闭。从门控跃迁的自由能曲线和无约束模拟中，我们得出结论，孤立的 GLIC 跨膜结构域的孔会自发关闭。打开孔的机械功主要作用于 M2-M3 环。因此，这个短而保守的环与细胞外结构域的强相互作用对于将配体结合与通道打开耦联至关重要。
