CLC氯通道蛋白的结构与功能关系的研究
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摘要
ClC氯通道蛋白是一类重要的离子通道蛋白,它们广泛存在于原核细胞和真核细胞中,包括哺乳动物中。它具有重要的生理功能,当它的功能缺失时会引起许多疾病,如肌强直,不孕不育,耳聋等。它在细菌中的同源物的晶体结构在2002年被测得。在此之后一系列实验研究出现,但是实验只能得到通道的宏观性质,对于微观分子机制却很少涉及,因此从分子角度研究它的结构与功能的关系具有非常重要的意义。我们利用分子动力学,连续静电计算,建模等方法,研究了ClC氯通道的结构和功能特性,揭示其微观机制。
1.提出ClC-0氯离子通道导电性质的三态多离子输运模型
我们提出了一个三态多离子输运模型,它能很好地解释氯离子通道ClC-0的导电特性。将速率理论用于此模型,得到电流-电压和电导率-浓度的关系。模型中的五个可调参数,是通过拟合野生型ClC-0和它的变异体K519C的实验数据得到的。作为检验,将这个模型得到的数据与采用其他计算和模拟方法得到的数据进行比较。结果表明,从这个模型计算出的不同氯离子占据态之间的能量差与通过解泊松-玻尔兹曼方程得到的结合自由能是一致的。从此模型得到的平均导电离子数和离子通过速率与实验上的结果也是一致的。根据这个模型,由于残基K519变异成C519产生的电导率的下降能被归结为K519C变异对各个态之间转换速率常数的影响。这个工作有助于人们理解ClC-0的导电机制。
2.研究ClC-ec1中残基变异对氯离子静电结合自由能的影响
ClC通道蛋白的残基变异导致蛋白功能的改变,引发许多疾病。现已查明,ClC蛋白功能的实现与氯离子在通道中的结合能密切相关。因此研究残基变异对ClC-ec1功能的影响可以通过研究残基变异对氯离子在通道中的结合能的影响来体现。我们系统地研究了各种残基变异对氯离子在通道中的结合能的影响。通过使用全原子分子动力学模拟和静电计算,揭示出残基变异引起的电荷变化和残基与氯离子结合位点的距离是影响氯离子结合能的重要因素。这一工作在分子层次上使人们认识了ClC通道蛋白的残基变异对蛋白功能影响的实质。
C1C proteins are found in both prokaryotic and eukaryotic cells. These proteins complete many important functional tasks, including the maintenance of membrane potential, the regulation of transepithelial chloride transport, and control of intravesicular pH. The physiological importance of these proteins can best be illustrated by the existence of hereditary diseases caused by defective C1C proteins. Dutzler et al. solved the three-dimensional structure of C1C proteins by resolving bacterial C1C homologs. Soon after Dutzler et al. solved the X-ray structure, others showed that the bacterial C1C homolog is not an ion channel but rather a Cl-/H+ exchange transporter with stoichiometry 2:1. Despite extensive experimental data, the molecular mechanism remains unclear. This paper using molecular dynamics simulation, continuous electrostatic calculation, and present a simple model to investigate the properties of ion permeation and conduction for C1C chloride proteins.
1. Present a three-state multi-ion kinetic model for conduction properties of C1C-0 chloride channel
A three-state multi-ion kinetic model was proposed that has enabled the conduction properties of the mammalian channel C1C-0 to be well characterized. Using this rate theory-based model the current-voltage and conductance-concentration relations were obtained. The five parameters in the model were determined by fitting the data of conduction experiments of the wild-type C1C-0 and its K519C mutant. The model was tested against available calculation and simulation data. The energy differences between distinct chloride-occupancy states computed from the model agree with an independent calculation on the binding free energies solved by using the Poisson-Boltzmann equation. The average ion number of conduction and the ion passing duration calculated using the model closely resemble the values obtained from Brownian dynamics simulations. According to the model the decrease of conductance caused by mutating residue K519 to C519 can be attributed to the effect of K519C mutation on translocation rate constants. Our study sets up a theoretical model for ion permeation and conductance in C1C-0. It would help understand the conduction mechanism of C1C-0
2. Investigate influence of residue mutation on binding free energy of chloride in EcC1C channel
Mutation of residue of C1C channel proteins causes serious functional change, even diseases. C1C protein function is related to the binding free energy of chloride at the binding sites, so the influence of residue mutation on function of EcC1C channels can be investigated through the effect of residue mutation on the binding free energy of chloride in EcC1C channels. This paper made a comprehensive investigation on the influence of residue mutation upon the binding free energy of chloride in EcC1C channels by using an all-atom molecular dynamics calculation. It also revealed the law how the charge change caused by residue mutation and the distance between residue and chloride govern the variation of the binding free energy. This work can help us understand the effect of residue mutation on the function of C1C channel proteins and then the relation between diseases and residue mutation.
1.提出ClC-0氯离子通道导电性质的三态多离子输运模型
我们提出了一个三态多离子输运模型,它能很好地解释氯离子通道ClC-0的导电特性。将速率理论用于此模型,得到电流-电压和电导率-浓度的关系。模型中的五个可调参数,是通过拟合野生型ClC-0和它的变异体K519C的实验数据得到的。作为检验,将这个模型得到的数据与采用其他计算和模拟方法得到的数据进行比较。结果表明,从这个模型计算出的不同氯离子占据态之间的能量差与通过解泊松-玻尔兹曼方程得到的结合自由能是一致的。从此模型得到的平均导电离子数和离子通过速率与实验上的结果也是一致的。根据这个模型,由于残基K519变异成C519产生的电导率的下降能被归结为K519C变异对各个态之间转换速率常数的影响。这个工作有助于人们理解ClC-0的导电机制。
2.研究ClC-ec1中残基变异对氯离子静电结合自由能的影响
ClC通道蛋白的残基变异导致蛋白功能的改变,引发许多疾病。现已查明,ClC蛋白功能的实现与氯离子在通道中的结合能密切相关。因此研究残基变异对ClC-ec1功能的影响可以通过研究残基变异对氯离子在通道中的结合能的影响来体现。我们系统地研究了各种残基变异对氯离子在通道中的结合能的影响。通过使用全原子分子动力学模拟和静电计算,揭示出残基变异引起的电荷变化和残基与氯离子结合位点的距离是影响氯离子结合能的重要因素。这一工作在分子层次上使人们认识了ClC通道蛋白的残基变异对蛋白功能影响的实质。
C1C proteins are found in both prokaryotic and eukaryotic cells. These proteins complete many important functional tasks, including the maintenance of membrane potential, the regulation of transepithelial chloride transport, and control of intravesicular pH. The physiological importance of these proteins can best be illustrated by the existence of hereditary diseases caused by defective C1C proteins. Dutzler et al. solved the three-dimensional structure of C1C proteins by resolving bacterial C1C homologs. Soon after Dutzler et al. solved the X-ray structure, others showed that the bacterial C1C homolog is not an ion channel but rather a Cl-/H+ exchange transporter with stoichiometry 2:1. Despite extensive experimental data, the molecular mechanism remains unclear. This paper using molecular dynamics simulation, continuous electrostatic calculation, and present a simple model to investigate the properties of ion permeation and conduction for C1C chloride proteins.
1. Present a three-state multi-ion kinetic model for conduction properties of C1C-0 chloride channel
A three-state multi-ion kinetic model was proposed that has enabled the conduction properties of the mammalian channel C1C-0 to be well characterized. Using this rate theory-based model the current-voltage and conductance-concentration relations were obtained. The five parameters in the model were determined by fitting the data of conduction experiments of the wild-type C1C-0 and its K519C mutant. The model was tested against available calculation and simulation data. The energy differences between distinct chloride-occupancy states computed from the model agree with an independent calculation on the binding free energies solved by using the Poisson-Boltzmann equation. The average ion number of conduction and the ion passing duration calculated using the model closely resemble the values obtained from Brownian dynamics simulations. According to the model the decrease of conductance caused by mutating residue K519 to C519 can be attributed to the effect of K519C mutation on translocation rate constants. Our study sets up a theoretical model for ion permeation and conductance in C1C-0. It would help understand the conduction mechanism of C1C-0
2. Investigate influence of residue mutation on binding free energy of chloride in EcC1C channel
Mutation of residue of C1C channel proteins causes serious functional change, even diseases. C1C protein function is related to the binding free energy of chloride at the binding sites, so the influence of residue mutation on function of EcC1C channels can be investigated through the effect of residue mutation on the binding free energy of chloride in EcC1C channels. This paper made a comprehensive investigation on the influence of residue mutation upon the binding free energy of chloride in EcC1C channels by using an all-atom molecular dynamics calculation. It also revealed the law how the charge change caused by residue mutation and the distance between residue and chloride govern the variation of the binding free energy. This work can help us understand the effect of residue mutation on the function of C1C channel proteins and then the relation between diseases and residue mutation.
引文
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