title: Simulations of Membrane-Disrupting Peptides I: Alamethicin Pore Stability and Spontaneous Insertion.
abstract: An all-atom molecular dynamics simulation of the archetype barrel-stave alamethicin (alm) pore in a 1,2-dioleoyl-sn-glycero-3-phosphocholine bilayer at 313 K indicates that ∼7 μs is required for equilibration of a preformed 6-peptide pore; the pore remains stable for the duration of the remaining 7 μs of the trajectory, and the structure factors agree well with experiment. A 5 μs simulation of 10 surface-bound alm peptides shows significant peptide unfolding and some unbinding, but no insertion. Simulations at 363 and 413 K with a -0.2 V electric field yield peptide insertion in 1 μs. Insertion is initiated by the folding of residues 3-11 into an α-helix, and mediated by membrane water or by previously inserted peptides. The stability of five alm pore peptides at 413 K with a -0.2 V electric field demonstrates a significant preference for a transmembrane orientation. Hence, and in contrast to the cationic antimicrobial peptide described in the following article, alm shows a strong preference for the inserted over the surface-bound state.
authors.affiliation: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: B Scott
authors.initials: BS
authors.lastname: Perrin
authors.affiliation: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: pastorr@nhlbi.nih.gov.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Pastor
mesh_terms: D000408:Alamethicin / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D004574:Electromagnetic Fields; D029941:Fish Proteins / Q000737:chemistry; D005399:Fishes; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism; D005997:Glycerylphosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D017510:Protein Folding; D014242:Trichoderma; D014783:Viscosity
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D029941:Fish Proteins; D005656:Fungal Proteins; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; C449802:moronecidin protein, Morone saxatilis; D000408:Alamethicin; D005997:Glycerylphosphorylcholine; C017251:1,2-oleoylphosphatidylcholine