The neuronal alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR) is a target for general anesthetics, Currently available experimental structural information is inadequate to understand where anesthetics bind and how they modulate the receptor motions essential to function. Using our published open-channel structure model of alpha 4 beta 2 nAChR, we identified and evaluated six amphiphilic interaction sites for the volatile anesthetic halothane via flexible ligand docking and subsequent 20-ns molecular dynamics simulations. Halothane binding energies ranged from -6.8 to -2.4 kcal/mol. The primary binding sites were located at the interface of extracellular and transmembrane domains, where halothane perturbed conformations of, and widened the gap among, the Cys loop, the beta 1-beta 2 loop, and the TM2-TM3 linker. The halothane with the highest binding affinity at the interface between the alpha 4 and beta 2 subunits altered interactions between the protein and nearby lipids by competing for hydrogen bonds. Gaussian network model analyses of the alpha 4 beta 2 nAChR structures at the end of 20-ns simulations in the absence of presence of halothane revealed profound changes in protein residue mobility. The concerted motions critical to protein function were also perturbed considerably. Halothane's effect oil protein dynamics was not confined to the residues adjacent to the binding sites, indicating all action on a more global scale.