Hui Chenggong, de Vries Reinier, Kopec Wojciech, de Groot Bert L
Computational Biomolecular Dynamics Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen 37077, Germany.
Department of Chemistry, Queen Mary University of London, London E1 4NS, United Kingdom.
Proc Natl Acad Sci U S A. 2025 May 27;122(21):e2423866122. doi: 10.1073/pnas.2423866122. Epub 2025 May 20.
Potassium (K) channels are widely distributed in many types of organisms. They combine high efficiency (100 pS) and K/Na selectivity by a conserved selectivity filter (SF). Molecular Dynamics (MD) simulations can provide detailed, atomistic mechanisms of this sophisticated ion permeation. However, currently there are clear inconsistencies between computational predictions and experimental results. First, the ion occupancy of the SF in simulations is lower than expected (2.5 in MD compared to ~4 in X-ray crystallography). Second, in many reported MD simulations of K channels, K conductance is typically an order of magnitude lower than experimental values. This discrepancy is in part because the force fields used in MD simulations of potassium channels do not account for polarization. One of the proposed solutions is the Electronic Continuum Correction (ECC), a force field modification that scales down formal charges, to introduce the polarization in a mean-field way. When the ECC is used in conjunction with the Charmm36m force field, the simulated K conductance increases 13-fold. Following the analysis of ion occupancy states using Hamiltonian Replica Exchange simulations, we propose a parameter set for Amber14sb, that also leads to a similar increase in conductance. These two force fields are then used to compute the full current-voltage (I-V) curves from MD simulations, approaching quantitative agreement with experiments at all voltages. In general, the ECC-enabled simulations are in excellent agreement with experiment, in terms of ion occupancy, conductance, current-voltage response, and K/Na selectivity.
钾（K）通道广泛分布于多种生物体中。它们通过一个保守的选择性过滤器（SF）实现了高效率（约100皮安）和K/Na选择性。分子动力学（MD）模拟可以提供这种复杂离子渗透的详细原子机制。然而，目前计算预测和实验结果之间存在明显的不一致。首先，模拟中SF的离子占有率低于预期（MD中约为2.5，而X射线晶体学中约为4）。其次，在许多报道的K通道MD模拟中，K电导通常比实验值低一个数量级。这种差异部分是因为钾通道MD模拟中使用的力场没有考虑极化。提出的解决方案之一是电子连续介质校正（ECC），这是一种力场修正，通过按比例降低形式电荷以平均场方式引入极化。当ECC与Charmm36m力场结合使用时，模拟的K电导增加了13倍。在使用哈密顿量副本交换模拟分析离子占有率状态后，我们为Amber14sb提出了一组参数，这也导致了类似的电导增加。然后使用这两个力场从MD模拟中计算完整的电流-电压（I-V）曲线，在所有电压下都接近与实验的定量一致。总体而言，启用ECC的模拟在离子占有率、电导、电流-电压响应和K/Na选择性方面与实验结果非常吻合。
