Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N1N4, Canada.
Center for Nonlinear Studies, Los Alamos National Lab, Los Alamos, New Mexico 87544, United States.
J Chem Theory Comput. 2021 Mar 9;17(3):1726-1741. doi: 10.1021/acs.jctc.0c00968. Epub 2021 Feb 4.
Despite the progress in modeling complex molecular systems of ever-increasing complexity, a quantitatively accurate computational treatment of ion permeation through narrow membrane channels remains challenging. An important factor to reach this goal is induced electronic polarization, which is likely to impact the permeation rate of small ions through narrow molecular pores. In this work, we extended the recently developed polarizable force field based on the classical Drude oscillators to assess the role of induced polarization effects on the energetics of sodium and potassium ion transport across the gramicidin A (gA) ion channel. The inclusion of induced polarization lowers barriers present in 1D potential of mean force (PMF) for cation permeation by ∼50% compared to those obtained with the additive force field. Conductance properties calculated with 1D PMFs from Drude simulations are in better agreement with experimental results. Polarization of single-file water molecules and protein atoms forming the narrow pore has a direct impact on the free-energy barriers and cation-specific solid-state NMR chemical shifts. Sensitivity analysis indicates that small changes to water-channel interactions can alter the free energy barrier for ion permeation. These results, illustrating polarization effects present in the complex electrostatic environment of the gA channel, have broad implications for revising proposed mechanisms of ion permeation and selectivity in a variety of ion channels.
尽管在模拟日益复杂的复杂分子系统方面取得了进展，但定量准确地计算通过狭窄膜通道的离子渗透仍然具有挑战性。实现这一目标的一个重要因素是感应电子极化，这可能会影响小离子通过狭窄分子孔的渗透速率。在这项工作中，我们扩展了最近开发的基于经典 Drude 振荡器的极化力场，以评估感应极化效应对穿过革兰氏菌素 A (gA) 离子通道的钠离子和钾离子传输的能量学的影响。与加和力场相比，感应极化的包含将阳离子渗透的一维平均力势能 (PMF) 中的势垒降低了约 50%。从 Drude 模拟的 1D PMFs 计算得出的电导率性质与实验结果更吻合。形成狭窄孔的单分子水分子和蛋白质原子的极化对自由能势垒和阳离子特异性固态 NMR 化学位移有直接影响。敏感性分析表明，对水通道相互作用的微小改变可以改变离子渗透的自由能势垒。这些结果说明了 gA 通道复杂静电环境中存在的极化效应，对修正各种离子通道中离子渗透和选择性的提出机制具有广泛的意义。
