Properties Of Protein Structure And Function For CLC-type Chloride Protein

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 channelA 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-02. Investigate influence of residue mutation on binding free energy of chloride in EcC1C channelMutation 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.