KINKED STRUCTURES OF ISOLATED NICOTINIC RECEPTOR M2 HELICES - A MOLECULAR-DYNAMICS STUDY

The pore-lining M2 helix of the nicotinic acetylcholine receptor exhib its a pronounced kink when the corresponding ion channel is in a close d conformation [N. Unwin (1993) Journal of Molecular Biology, Vol. 229 , pp. 1101-1124]. We have performed molecular dynamics simulations of isolated 22-residue M2 helices in order to identify a possible molecul ar origin of this kink. In order to sample a wide range of conformatio nal space, a simulated annealing protocol was used to generate five in itial M2 helix structures, each of which was subsequently used as the basis of 300 ps MD simulations. Two helix sequences (M2 alpha and M2 d elta) were studied in this manner, resulting in a total of ten 300 ps trajectories. Kinked helices present in the trajectories were identifi ed and energy minimized to yield a total of five different stable kink ed structures. For comparison, a similar molecular dynamics simulation of a Leu(23) helix yielded no stable kinked structures. In four of th e five kinked helices, the kink was stabilized by H bonds between the helix backbone and polar sidechain atoms. Comparison with data from th e literature on site-directed mutagenesis of M2 residues suggests that such polar side-chain to main-chain H bonds may also contribute to ki nking of M2 helices in the intact channel protein. (C) 1994 John Wiley & Sons, Inc.