We use stochastic simulations to investigate the performance of two recently developed methods for calculating the free energy profiles of ion channels and their electrophysiological properties, such as current–voltage dependence and reversal potential, from molecular dynamics simulations at a single applied voltage. These methods require neither knowledge of the diffusivity nor simulations at multiple voltages, which greatly reduces the computational effort required to probe the electrophysiological properties of ion channels. They can be used to determine the free energy profiles from either forward or backward one-sided properties of ions in the channel, such as ion fluxes, density profiles, committor probabilities, or from their two-sided combination. By generating large sets of stochastic trajectories, which are individually designed to mimic the molecular dynamics crossing statistics of models of channels of trichotoxin, p7 from hepatitis C and a bacterial homolog of the pentameric ligand-gated ion channel, GLIC, we find that the free energy profiles obtained from stochastic simulations corresponding to molecular dynamics simulations of even a modest length are burdened with statistical errors of only 0.3 kcal/mol. Even with many crossing events, applying two-sided formulas substantially reduces statistical errors compared to one-sided formulas. With a properly chosen reference voltage, the current–voltage curves can be reproduced with good accuracy from simulations at a single voltage in a range extending for over 200 mV. If possible, the reference voltages should be chosen not simply to drive a large current in one direction, but to observe crossing events in both directions.

中文翻译：

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单电压计算的电生理特性：带有随机模拟的测试理论

我们使用随机模拟来研究两种最新开发的方法的性能，这些方法用于通过单个施加电压下的分子动力学模拟来计算离子通道的自由能曲线及其电生理特性，例如电流-电压依赖性和反转电位。这些方法既不需要了解扩散率，也不需要在多个电压下进行仿真，从而极大地减少了探测离子通道电生理特性所需的计算量。它们可用于根据通道中离子的向前或向后单侧属性（例如离子通量，密度分布，定能子概率）或从其两侧组合来确定自由能分布。通过产生大量的随机轨迹，分别设计为模拟来自丙型肝炎的滴虫毒素p7通道和五聚体配体门控离子通道GLIC的细菌同源物模型的分子动力学交叉统计，我们发现从随机模拟获得的自由能谱对应于即使是中等长度的分子动力学模拟，其统计误差也仅为0.3 kcal / mol。即使存在许多交叉事件，与单侧公式相比，应用双侧公式仍会大大减少统计误差。With a properly chosen reference voltage, the current–voltage curves can be reproduced with good accuracy from simulations at a single voltage in a range extending for over 200 mV. 如果可能，应该选择参考电压，而不仅仅是在一个方向上驱动大电流，