School of Science , RMIT University , Melbourne , Victoria 3000 , Australia.
Department of Physiology & Membrane Biology/Department of Pharmacology , University of California , Davis , 95616 , United States.
Chem Rev. 2019 Jul 10;119(13):7737-7832. doi: 10.1021/acs.chemrev.8b00630. Epub 2019 Jun 27.
Membrane ion channels are the fundamental electrical components in the nervous system. Recent developments in X-ray crystallography and cryo-EM microscopy have revealed what these proteins look like in atomic detail but do not tell us how they function. Molecular dynamics simulations have progressed to the point that we can now simulate realistic molecular assemblies to produce quantitative calculations of the thermodynamic and kinetic quantities that control function. In this review, we summarize the state of atomistic simulation methods for ion channels to understand their conduction, activation, and drug modulation mechanisms. We are at a crossroads in atomistic simulation, where long time scale observation can provide unbiased exploration of mechanisms, supplemented by biased free energy methodologies. We illustrate the use of these approaches to describe ion conduction and selectivity in voltage-gated sodium and acid-sensing ion channels. Studies of channel gating present a significant challenge, as activation occurs on longer time scales. Enhanced sampling approaches can ensure convergence on minimum free energy pathways for activation, as illustrated here for pentameric ligand-gated ion channels that are principal to nervous system function and the actions of general anesthetics. We also examine recent studies of local anesthetic and antiepileptic drug binding to a sodium channel, revealing sites and pathways that may offer new targets for drug development. Modern simulations thus offer a range of molecular-level insights into ion channel function and modulation as a learning platform for mechanistic discovery and drug development.
膜离子通道是神经系统的基本电元件。X 射线晶体学和冷冻电镜显微镜的最新发展揭示了这些蛋白质在原子细节上的样子，但并没有告诉我们它们是如何发挥作用的。分子动力学模拟已经发展到我们现在可以模拟真实的分子组装，从而对控制功能的热力学和动力学数量进行定量计算的地步。在这篇综述中，我们总结了离子通道的原子模拟方法的现状，以了解它们的传导、激活和药物调节机制。我们正处于原子模拟的十字路口，在这个阶段，长时间尺度的观察可以为机制提供无偏探索，并辅以有偏自由能方法。我们举例说明了这些方法在描述电压门控钠离子和酸感应离子通道中的离子传导和选择性方面的应用。通道门控的研究提出了一个重大挑战，因为激活发生在更长的时间尺度上。增强采样方法可以确保激活的最小自由能途径的收敛，正如这里对五聚体配体门控离子通道的研究所示，这些通道对神经系统功能和全身麻醉剂的作用至关重要。我们还研究了局部麻醉剂和抗癫痫药物与钠离子通道结合的最新研究，揭示了可能为药物开发提供新靶点的结合位点和途径。因此，现代模拟为离子通道功能和调节提供了一系列分子水平的见解，作为机制发现和药物开发的学习平台。
