Mutations in ClC channel proteins may cause serious functional changes and even diseases. The function of ClC proteins mainly manifests as Cl^– transport, which is related to the binding free energies of chloride ions. Therefore, the influence of a mutation on ClC function can be studied by investigating the mutational effect on the binding free energies of chloride ions. The present study provides quantitative and systematic investigations on the influences of residue mutations on the electrostatic binding free energies in Escherichia coli ClC (EcClC) proteins, using all-atom molecular dynamics simulations. It was found that the change of the electrostatic binding free energy decreases linearly with the increase of the residue–chloride ion distance for a mutation. This work reveals how changes in the charge of a mutated residue and in the distance between the mutated residue and the binding site govern the variations in the electrostatic binding free energies and therefore influence the transport of chloride ions and conduction in EcClC. This work would facilitate our understanding of the mutational effects on transport of chloride ions and functions of ClC proteins and provide a guideline to estimate which residue mutations will have great influences on ClC functions.

中文翻译：

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突变对大肠杆菌 ClC 中氯离子静电结合自由能的影响

ClC 通道蛋白的突变可能会导致严重的功能变化甚至疾病。的ClC蛋白主要体现为Cl组成的功能^-传输，这与氯离子的结合自由能。因此，可以通过研究突变对氯离子结合自由能的影响来研究突变对 ClC 功能的影响。本研究对残基突变对大肠杆菌静电结合自由能的影响进行了定量和系统的研究。ClC (EcClC) 蛋白质，使用全原子分子动力学模拟。发现静电结合自由能的变化随着突变的残基-氯离子距离的增加而线性降低。这项工作揭示了突变残基电荷的变化以及突变残基与结合位点之间距离的变化如何控制静电结合自由能的变化，从而影响氯离子的传输和 EcClC 中的传导。这项工作将有助于我们了解对氯离子转运和 ClC 蛋白功能的突变影响，并为估计哪些残基突变将对 ClC 功能产生重大影响提供指导。