title: Molecular dynamics investigation of Cl(-) transport through the closed and open states of the 2α12β2γ2 GABA(A) receptor.
abstract: The α1β2γ2 gamma-aminobutyric type A receptor (GABA(A)R) is one of the most widely expressed GABA(A)R subtypes in the mammalian brain. GABA(A)Rsbelonging 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 GABA(A)R was constructed using the structure of the glutamate-gated chloride channel (GluCl), which has a high sequence identity to GABA(A)R. A closed-state model was constructed using the structure of the nicotinic acetylcholine receptor (nAChR). Molecular dynamics simulations of the open-state and closed-state GABA(A)R 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 GABA(A)R. Then, the free-energy of chloride ion permeations through the closed-state and open-state G GABA(A)R has been estimated using adaptive biasing force (ABF) simulation. For the closed-state G GABA(A)R, we observed two major energy barriers for chloride ion translocation in the transmembrane domain (TMD). For the open-state GABA(A)R, 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 GABA(A)R, which gives a complete map of the ion channel of Cl(-) permeation.
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Xie
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Sha
authors.forename: Mao-Sheng
authors.initials: MS
authors.lastname: Cheng
mesh_terms: D000595:Amino Acid Sequence; D002712:Chlorides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism; D017136:Ion Transport; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D055672:Static Electricity
chemical_list: D002712:Chlorides; D007473:Ion Channels; D021122:Protein Subunits; D011963:Receptors, GABA-A
keywords: Adaptive biasing force (ABF); Gamma-aminobutyric type A receptor (GABA(A)R); Homology modeling; Molecular dynamics (MD) simulation