S N Bose National Centre For Basic Sciences, Salt Lake, Kolkata 700098, India.
J Chem Phys. 2013 Apr 28;138(16):165102. doi: 10.1063/1.4801999.
In this paper, we have explored generic criteria of cooperative behavior in ion channel kinetics treating it on the same footing with multistate receptor-ligand binding in a compact theoretical framework. We have shown that the characterization of cooperativity of ion channels in terms of the Hill coefficient violates the standard Hill criteria defined for allosteric cooperativity of ligand binding. To resolve the issue, an alternative measure of cooperativity is proposed here in terms of the cooperativity index that sets a unified criteria for both the systems. More importantly, for ion channel this index can be very useful to describe the cooperative kinetics as it can be readily determined from the experimentally measured ionic current combined with theoretical modelling. We have analyzed the correlation between the voltage value and slope of the voltage-activation curve at the half-activation point and consequently determined the standard free energy of activation of the ion channel using two well-established mechanisms of cooperativity, namely, Koshland-Nemethy-Filmer (KNF) and Monod-Wyman-Changeux (MWC) models. Comparison of the theoretical results for both the models with appropriate experimental data of mutational perturbation of Shaker K(+) channel supports the experimental fact that the KNF model is more suitable to describe the cooperative behavior of this class of ion channels, whereas the performance of the MWC model is unsatisfactory. We have also estimated the mechanistic performance through standard free energy of channel activation for both the models and proposed a possible functional disadvantage in the MWC scheme.
在本文中，我们探讨了离子通道动力学中的通用合作标准，将其与多态受体配体结合在一个紧凑的理论框架中进行处理。我们表明，用 Hill 系数来描述离子通道的协同性与配体结合的变构协同性的标准 Hill 标准不符。为了解决这个问题，本文提出了一种协同性的替代度量标准，即协同指数，为这两个系统设定了统一的标准。更重要的是，对于离子通道，这个指数可以非常有用，因为它可以根据实验测量的离子电流与理论模型相结合来描述协同动力学。我们分析了在半激活点处电压激活曲线的电压值和斜率之间的相关性，并根据两种已建立的协同机制，即 Koshland-Nemethy-Filmer（KNF）和 Monod-Wyman-Changeux（MWC）模型，确定了离子通道的标准自由能活化。对这两种模型的理论结果与 Shaker K(+)通道突变扰动的适当实验数据进行比较，支持了 KNF 模型更适合描述这类离子通道协同行为的实验事实，而 MWC 模型的性能则不尽如人意。我们还通过两种模型的通道活化标准自由能来估计其机械性能，并提出了 MWC 方案可能存在的功能缺陷。
