Molecular dynamics investigation of Cl-transport through the closed and open states of the 2α12β2γ2 GABAA receptor
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.
Gamma-aminobutyric type A receptor (GABAAR) Homology modeling Molecular dynamics (MD) simulation Adaptive biasing force (ABF)
Hong-Bo Xie Jian Wang Yu Sha Mao-Sheng Cheng
Key Laboratory of Structure-Based Drugs Deign &Discovery of Ministry of Education, School of Pharmaceutical Engineering Shenyang Pharmaceutical University, Shenyang 110016, PR China
国内会议
苏州
英文
264-272
2014-10-26（万方平台首次上网日期，不代表论文的发表时间）