Exobiology Branch, MS239-4, NASA Ames Research Center, Moffett Field, California 94035, United States.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94132, United States.
J Phys Chem B. 2021 Apr 1;125(12):3132-3144. doi: 10.1021/acs.jpcb.0c10737. Epub 2021 Mar 17.
The availability of high-resolution structures of ion channels opens the doors to reliable computations of electrophysiological properties, such as the dependence of ionic currents and selectivities on applied voltage. We develop two theoretical approaches for calculating these properties from molecular dynamics simulations at a single voltage, or even in the absence of voltage, combined with the electrodiffusion model in which ion motion in the channel is represented as one-dimensional diffusion in the potential of mean force exerted by other components of the system and the applied electric field. No knowledge of diffusivity or ion densities at other voltages is needed. Instead, in one approach, one-sided ion fluxes and density profiles are used to determine the free energy profile. In the other approach, committor probabilities for ions transported at the selected voltage are used for this purpose. Both approaches have been validated in an example of a simple ion channel formed by trichotoxin. The potentials of mean force calculated by way of the proposed approaches and obtained from traditional methods are in excellent agreement. Furthermore, the current-voltage dependence agrees very well with results obtained by way of computationally more demanding methods. We also have readily calculated the reversal potential, a computationally challenging electrophysiological property. The key assumptions of the electrodiffusion model, such as the independence of crossing events or the insensitivity of the potential of mean force to applied voltage, have been found to be satisfied. We also show that the voltage changes linearly in the hydrophobic core of the membrane and is constant elsewhere.
离子通道的高分辨率结构的可用性为可靠计算电生理特性（如离子电流和选择性对施加电压的依赖性）打开了大门。我们开发了两种理论方法，用于从单个电压下的分子动力学模拟，甚至在没有电压的情况下，结合电扩散模型来计算这些特性，其中离子在通道中的运动表示为系统其他组成部分和施加电场的平均力势中的一维扩散。不需要其他电压下的扩散率或离子密度的知识。相反，在一种方法中，单边离子通量和密度分布用于确定自由能分布。在另一种方法中，选择电压下运输的离子的易位概率用于此目的。这两种方法都在由 Trichotoxin 形成的简单离子通道的示例中得到了验证。通过所提出的方法计算的平均力势与通过传统方法获得的平均力势非常吻合。此外，电流-电压关系与通过计算要求更高的方法获得的结果非常吻合。我们还很容易地计算了反转电位，这是一种计算上具有挑战性的电生理特性。电扩散模型的关键假设，如穿越事件的独立性或平均力势对施加电压的不敏感性，已经得到满足。我们还表明，电压在膜的疏水区线性变化，而在其他地方保持不变。
