PARALLEL HELIX BUNDLES AND ION CHANNELS - MOLECULAR MODELING VIA SIMULATED ANNEALING AND RESTRAINED MOLECULAR-DYNAMICS

A parallel bundle of transmembrane (TM) alpha-helices surrounding a ce ntral pore is present in several classes of ion channel, including the nicotinic acetylcholine receptor (nAChR). We have modeled bundles of hydrophobic and of amphipathic helices using simulated annealing via r estrained molecular dynamics. Bundles of Ala,, helices, with N = 4, 5, or 6 helices/bundle were generated. For all three N values the helice s formed left-handed coiled coils, with pitches ranging from 160 Angst rom (N = 4) to 240 Angstrom (N = 6). Pore radius profiles revealed con strictions at residues 3, 6, 10, 13, and 17. A left-handed coiled coil and a similar pattern of pore constrictions were observed for N = 5 b undles of Leu(20). in contrast, N = 5 bundles of Ile(20) formed right- handed coiled coils, reflecting loosened packing of helices containing beta-branched side chains. Bundles formed by each of two classes of a mphipathic helices were examined: (a) M2a, M2b, and M2c derived from s equences of M2 helices of nAChR; and (6) (LSSLLSL)(3), a synthetic cha nnel-forming peptide. Both classes of amphipathic helix formed left-ha nded coiled coils. For (LSSLLSL)(3) the pitch of the coil increased as N increased from 4 to 6. The M2c N = 5 helix bundle is discussed in t he context of possible models of the pore domain of nAChR.