title: On the nature of antimicrobial activity: a model for protegrin-1 pores.
abstract: We conducted over 150 ns of simulation of a protegrin-1 octamer pore in a lipid bilayer composed of palmitoyloleoyl-phosphatidylethanolamine (POPE) and palmitoyloleoyl-phosphatidylglycerol (POPG) lipids mimicking the inner membrane of a bacterial cell. The simulations improve on a model of a pore proposed from recent NMR experiments and provide a coherent understanding of the molecular mechanism of antimicrobial activity. Although lipids tilt somewhat toward the peptides, the simulated protegrin-1 pore more closely follows the barrel-stave model than the toroidal-pore model. The movement of ions is investigated through the pore. The pore selectively allows negatively charged chloride ions to pass through at an average rate of one ion every two nanoseconds. Only two events are observed of sodium ions crossing through the pore. The potential of mean force is calculated for the water and both ion types. It is determined that the chloride ions move through the pore with ease, similarly to the water molecules with the exception of a zone of restricted movement midway through the pore. In bacteria, ions moving through the pore will compromise the integrity of the transmembrane potential. Without the transmembrane potential as a countermeasure, water will readily flow inside the higher osmolality cytoplasm. We determine that the diffusivity of water through a single PG-1 pore is sufficient to cause fast cell death by osmotic lysis.
authors.affiliation: Department of Chemical Engineering and Materials Science, 421 Washington Avenue SE, Minneapolis, Minnesota 55455, USA.
authors.forename: Allison A
authors.initials: AA
authors.lastname: Langham
authors.forename: Abdallah Sayyed
authors.initials: AS
authors.lastname: Ahmad
authors.forename: Yiannis N
authors.initials: YN
authors.lastname: Kaznessis
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D002712:Chlorides / Q000737:chemistry; D003198:Computer Simulation; D004926:Escherichia coli / Q000187:drug effects; D017136:Ion Transport; D008051:Lipid Bilayers / Q000737:chemistry; D008089:Listeria monocytogenes / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008958:Models, Molecular; D009994:Osmolar Concentration; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology; D012964:Sodium / Q000737:chemistry; D013997:Time Factors; D014867:Water / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D002712:Chlorides; D008051:Lipid Bilayers; D010714:Phosphatidylethanolamines; D010715:Phosphatidylglycerols; D011506:Proteins; C094880:protegrin-1; D014867:Water; C057561:1-palmitoyl-2-oleoylphosphatidylethanolamine; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol; D012964:Sodium