BUNDLES OF AMPHIPATHIC TRANSMEMBRANE ALPHA-HELICES AS A STRUCTURAL MOTIF FOR ION-CONDUCTING CHANNEL PROTEINS - STUDIES ON SODIUM-CHANNELS AND ACETYLCHOLINE-RECEPTORS

Channel proteins are transmembrane symmetric (or pseudosymmetric) oligomers organized around a central ionic pore. We present here a molecular model of the pore forming structures of two channel proteins with different primary structures and oligomeric size: the voltage‐sensitive sodium channel and the nicotinic cholinergic receptor. We report low‐energy arrangements of α‐helical bundles calculated by semiempiricial potential energy functions and optimization routines and further refined using molecular dynamics. The ion‐conducting pore is considered to be a symmetric or pseudosymmetric homooligomer of 3–5 amphipathic α‐helices arranged such that the polar residues line a central hydrophilic pathway and the apolar residues face the hydrophobic bilayer interior. The channel lining exposes either charged (Asp, Glu, Arg, Lys) or polar‐neutral (Ser, Thr) residues. A bundle of four parallel helices constrained to C4 symmetry, the helix axis aligned with the symmetry axis, and the helices constrained to idealized dihedral angles, produces a structure with a pore of the size inferred for the sodium channel protein (area ∼ 16 Å2). Similarly, a pentameric array optimized with constraints to maintain C5 symmetry and backbone torsions characteristic of α‐helices adopts a structure that appears well suited to form the lining of the nicotinic cholinergic receptor (pore area ∼ 46 Å2). Thus, bundles of amphipathic α‐helices satisfy the structural, energetic, and dynamic requirements to be the molecular structural motif underlying the function of ionic channels. Copyright © 1990 Wiley‐Liss, Inc.