Structure and dynamics of the pore-lining helix of the nicotinic receptor:MD simulations in water, lipid bilayers, and transbilayer bundles

Multiple nanosecond duration molecular dynamics simulations on the pore-lin ing M2 helix of the nicotinic acetylcholine receptor reveal how its structu re and dynamics change as a function of environment. In water, the M2 helix partially unfolds to form a molecular hinge in the vicinity of a central L eu residue that has been implicated in the mechanism of ion channel gating, In a phospholipid bilayer, either as a single transmembrane helix, or as p art of a pentameric helix bundle, the M2 helix shows less flexibility, but still exhibits a kink in the vicinity of the central Leu. The single M2 hel ix tilts relative to the bilayer normal by 12 degrees, in agreement with re cent solid state NMR data (Opella et al., Nat Struct Biol 6:374-379, 1999), The pentameric helix bundle, a model for the pore domain of the nicotinic receptor and for channels formed by M2 peptides in a bilayer, is remarkably stable over a 2-ns MD simulation in a bilayer, provided one adjusts the pK (A)s of ionizable residues to their calculated values (when taking their en vironment into account) before starting the simulation. The resultant trans bilayer pore shows fluctuations at either mouth which transiently close the channel. (C) 2000 Wiley-Liss, Inc.