【摘 要】
：
The α1β2γ2 gamma-aminobutyric type A receptor (GABAAR) is one of the most widely expressed GABAAR sub-types in the mammalian brain.GABAARs belonging to the Cys-loop superfamily of ligand-gated ion cha
【机 构】
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Key Laboratory of Structure-Based Drugs Deign &Discovery of Ministry of Education, School of Pharmac
【出 处】
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第七届国际分子模拟与信息技术应用学术会议
论文部分内容阅读
The α1β2γ2 gamma-aminobutyric type A receptor (GABAAR) is one of the most widely expressed GABAAR sub-types in the mammalian brain.GABAARs belonging to the Cys-loop superfamily of ligand-gated ion channels have been identified as key targets for many clinical drugs, and the motions that govern the gating mechanism are still not well understood.In this study, an open-state GABAAR was constructed using the structure of the glutamate-gated chloride channel (GluCl), which has a high sequence identity to GABAAR.A dosed-state model was constructed using the structure of the nicotinic acetylcholine receptor {nAChR).Molecular dynamics simulations of the open-state and closed-state GABAAR were performed.We calculated the electrostatic potential of the two conformations, the pore radius of the two ion channels and the root-mean-square fluctuation.We observed the presence of two positively charged girdles around the ion channel and found flexible regions in the GABAAR.Then, the free-energy of chloride ion permeations through the dosed-state and open-state GABAAR has been estimated using adaptive biasing force {ABF) simulation.For the dosed-state GABAAR, we observed two major energy barriers for chloride ion translocation in the transmembrane domain (TMD).For the open-state GABAAR, there was only one energy barrier formed by two Thr261 (α1), two Thr255 (β2) and one Thr271 (γ2).By using ABF simulation, the overall free-energy profile is obtained for Cl transporting through GABAAK which gives a complete map of the ion channel of Cl permeation.
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