The neuronal alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR) is a potential molecular target for general anesthetics. It is unclear, however, whether anesthetic action produces the same effect oil the open and closed channels. Computations parallel to Our previous open channel Study (J. Phys. Chem. B 2009, 113, 12581) were performed oil the closed-channel alpha 4 beta 2 nAChR to investigate the conformation-dependent anesthetic effects oil channel Structures and dynamics. Flexible ligand docking and over 20 ns molecular dynamics simulations revealed similar halothane-binding sites in the closed and open channels. The sites with relatively high binding affinities (similar to -6.0 kcal/mol) were identified at the interface of extracellular (EC) and transmembrane (TM) domains or at the interface between alpha 4 and beta 2 Subunits. Despite similar sites for halothane binding, the closed-channel conformation showed much less sensitivity than the open channel to the structural and dynamical perturbations from halothane. Compared to the systems Without anesthetics, the amount of water inside the pore decreased by 22% in the presence of halothane in the open channel but only by 6% in the closed channel. Comparison of the nonbonded interactions at the EC/TM interfaces suggested that the beta 2 Subunits were more prone than the alpha 4 subunits to halothane binding. In addition, our data Support the notion that halothane exerts its effect by disturbing the quaternary structure and dynamics of the channel. The study Concludes that sensitivity and global dynamics responsiveness of alpha 4 beta 2 nAChR to halothane are conformation dependent. The effect of halothane on the global dynamics of the open-channel conformation might also account for the action of other inhaled general anesthetics.