Data_Sheet_1_Asymmetric Interplay Between K+ and Blocker and Atomistic Parameters From Physiological Experiments Quantify K+ Channel Blocker Release.xlsx

Modulating the activity of ion channels by blockers yields information on both the mode of drug action and on the biophysics of ion transport. Here we investigate the interplay between ions in the selectivity filter (SF) of K+ channels and the release kinetics of the blocker tetrapropylammonium in the model channel KcvNTS. A quantitative expression calculates blocker release rate constants directly from voltage-dependent ion occupation probabilities in the SF. The latter are obtained by a kinetic model of single-channel currents recorded in the absence of the blocker. The resulting model contains only two adjustable parameters of ion-blocker interaction and holds for both symmetric and asymmetric ionic conditions. This data-derived model is corroborated by 3D reference interaction site model (3D RISM) calculations on several model systems, which show that the K+ occupation probability is unaffected by the blocker, a direct consequence of the strength of the ion-carbonyl attraction in the SF, independent of the specific protein background. Hence, KcvNTS channel blocker release kinetics can be reduced to a small number of system-specific parameters. The pore-independent asymmetric interplay between K+ and blocker ions potentially allows for generalizing these results to similar potassium channels.

通过调节离子通道的活性，阻断剂的应用不仅揭示了药物作用机制，亦揭示了离子传输的生物物理学特性。本研究旨在探讨钾离子通道（K+）选择性过滤器（SF）中的离子与阻断剂四丙基铵在模型通道KcvNTS中的释放动力学之间的相互作用。通过一个定量表达式，我们能够直接从选择性过滤器中的电压依赖性离子占据概率计算出阻断剂的释放速率常数。后者通过记录无阻断剂存在时的单通道电流的动力学模型获得。所得到的模型仅包含两个可调节的离子-阻断剂相互作用参数，且适用于对称和不对称的离子条件。此数据驱动的模型得到了在多个模型系统上进行的3D参考相互作用位点模型（3D RISM）计算的证实，这些计算表明钾离子占据概率不受阻断剂的影响，这是选择性过滤器中离子-羰基吸引力强度的直接后果，这种吸引力与特定的蛋白质背景无关。因此，KcvNTS通道阻断剂的释放动力学可以简化为少数系统特定的参数。钾离子与阻断剂离子之间孔隙无关的不对称相互作用可能允许将这些结果推广到类似的钾离子通道。