Simplified Models of the Pore Domain of the Nicotinic Acetylcholine Receptor

Abstract

The nicotinic acetylcholine receptor (nAChR) is a cation selective, ligand-gated ion channel. The pore is formed by five homlogous M2 transmembrane helices arranged pseudosymmetrically about a central axis [l]. In the absence of an atomic resolution structure for the receptor, we have used simulated annealing via molecular dynamics (SNMD) to investigate possible models for the pore. The SNMD procedure used is derived from that used to correctly predict the structure of the GCN4 leucine zipper [2]. It is based on molecular dynamics simulations in the presence of interhelix distance constraints. The starting point is a Ca template made up of an exactly parallel bundle of 5 idealized a-helices. The remaining backbone and sidechain atoms are built automatically by simulated annealing during which the Ca atoms are fixed. Ca restraints are then gradually released whilst atomic charges are scaled up to their final values. Distance restraints ensure pseudo-symmetry of the helix bundles during the final (5 ps) burst of molecular dynamics. The overall procedure is repeated to generate ensembles of 20 structures for each model.