title: Simulations of Membrane-Disrupting Peptides II: AMP Piscidin 1 Favors Surface Defects over Pores.
abstract: Antimicrobial peptides (AMPs) that disrupt bacterial membranes are promising therapeutics against the growing number of antibiotic-resistant bacteria. The mechanism of membrane disruption by the AMP piscidin 1 was examined with multimicrosecond all-atom molecular dynamics simulations and solid-state NMR spectroscopy. The primary simulation was initialized with 20 peptides in four barrel-stave pores in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol bilayer. The four pores relaxed to toroidal by 200 ns, only one porelike structure containing two transmembrane helices remained at 26 μs, and none of the 18 peptides released to the surface reinserted to form pores. The simulation was repeated at 413 K with an applied electric field and all peptides were surface-bound by 200 ns. Trajectories of surface-bound piscidin with and without applied fields at 313 and 413 K and totaling 6 μs show transient distortions of the bilayer/water interface (consistent with (31)P NMR), but no insertion to transmembrane or pore states. (15)N chemical shifts confirm a fully surface-bound conformation. Taken together, the simulation and experimental results imply that transient defects rather than stable pores are responsible for membrane disruption by piscidin 1, and likely other AMPs.
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: National High Magnetic Field Laboratory, Tallahassee, Florida.
authors.forename: Riqiang
authors.initials: R
authors.lastname: Fu
authors.affiliation: Department of Applied Science, The College of William & Mary, Williamsburg, Virginia.
authors.forename: Myriam L
authors.initials: ML
authors.lastname: Cotten
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: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism; D029941:Fish Proteins / Q000737:chemistry* / Q000378:metabolism; D005399:Fishes; D008051:Lipid Bilayers / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D000072756:Protein Conformation, alpha-Helical; D055550:Protein Stability; D013499:Surface Properties; D014867:Water / Q000737:chemistry
chemical_list: D023181:Antimicrobial Cationic Peptides; D029941:Fish Proteins; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; C449802:moronecidin protein, Morone saxatilis; D014867:Water; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine