title: Simulation studies of alamethicin-bilayer interactions.
abstract: Alamethicin is an alpha-helical peptide that forms voltage-activated ion channels. Experimental data suggest that channel formation occurs via voltage-dependent insertion of alamethicin helices into lipid bilayers, followed by self-assembly of inserted helices to form a parallel helix bundle. Changes in the kink angle of the alamethicin helix about its central proline residue have also been suggested to play a role in channel gating. Alamethicin helices generated by simulated annealing and restrained molecular dynamics adopt a kink angle similar to that in the x-ray crystal structure, even if such simulations start with an idealized unkinked helix. This suggests that the kinked helix represents a stable conformation of the molecule. Molecular dynamics simulations in the presence of a simple bilayer model and a transbilayer voltage difference are used to explore possible mechanisms of helix insertion. The bilayer is represented by a hydrophobicity potential. An alamethicin helix inserts spontaneously in the absence of a transbilayer voltage. Application of a cis positive voltage decreases the time to insertion. The helix kink angle fluctuates during the simulations. Insertion of the helix is associated with a decrease in the mean kink angle, thus helping the alamethicin molecule to span the bilayer. The simulation results are discussed in terms of models of alamethicin channel gating.
authors.affiliation: Laboratory of Molecular Biophysics, University of Oxford, England.
authors.forename: P C
authors.initials: PC
authors.lastname: Biggin
authors.forename: J
authors.initials: J
authors.lastname: Breed
authors.forename: H S
authors.initials: HS
authors.lastname: Son
authors.forename: M S
authors.initials: MS
authors.lastname: Sansom
mesh_terms: D000408:Alamethicin / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism*; D008564:Membrane Potentials; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D007473:Ion Channels; D008051:Lipid Bilayers; D000408:Alamethicin