MODELING PACKING INTERACTIONS IN PARALLEL HELIX BUNDLES - PENTAMERIC BUNDLES OF NICOTINIC RECEPTOR M2 HELICES

The transbilayer pore of the nicotinic acetylcholine receptor (nAChR) is formed by a pentameric bundle of M2 helices. Models of pentameric b undles of M2 helices have been generated using simulated annealing via restrained molecular dynamics, The influence of: (a) the initial C al pha template; and (b) screening of sidechain electrostatic interaction s on the geometry of the resultant M2 helix bundles is explored. Paral lel M2 helices, in the absence of sidechain electrostatic interactions , pack in accordance with simple ridges-in-grooves considerations. Thi s results in a helix crossing angle of ca. + 12 degrees, corresponding to a left-handed coiled coil structure for the bundle as a whole. Til ting of M2 helices away from the central pore axis at their C-termini acid/or inclusion of sidechain electrostatic interactions may perturb such ridges-in-grooves packing. In the most extreme cases right-handed coiled coils are formed. An interplay between inter-helix H-bonding a nd helix bundle geometry is revealed. The effects of changes in electr ostatic screening on the dimensions of the pore mouth are described an d the significance of these changes in the context of models for the n AChR pore domain is discussed.