Paper Citing NAMD - Abstract
Xie, Hong-Bo; Wang, Jian; Sha, Yu; Cheng, Mao-Sheng
Molecular dynamics investigation of Cl- transport through the closed and open states of the 2 alpha(1)2 beta(2)gamma(2) GABA(A) receptor
BIOPHYSICAL CHEMISTRY, 180:1-9, OCT-NOV 2013
The alpha(1)beta(2)gamma(2) gamma-aminobutyric type A receptor (GABA(A)R) is one of the most widely expressed GABA(A)R sub-types in the mammalian brain. GABA(A)Rs 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 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 GABA(A)R has been estimated using adaptive biasing force (ABF) simulation. For the closed-state 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 (alpha(1)), two Thr255 (beta(2)) and one Thr271 (gamma(2)). 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. (C) 2013 Elsevier B.V. All rights reserved.
