title: Interaction of protegrin-1 with lipid bilayers: membrane thinning effect.
abstract: Protegrins (PG) are important in defending host tissues, preventing infection via an attack on the membrane surface of invading microorganisms. Protegrins have powerful antibiotic abilities, but the molecular-level mechanisms underlying the interactions of their beta-sheet motifs with the membrane are not known. Protegrin-1 (PG-1) is composed of 18 amino acids with a high content of basic residues and two disulfide bonds. Here we focused on the stability of PG-1 at the amphipathic interface in lipid bilayers and on the details of the peptide-membrane interactions. We simulated all-atom models of the PG-1 monomer with explicit water and lipid bilayers composed of both homogeneous POPC (palmitoyl-oleyl-phosphatidylcholine) lipids and a mixture of POPC/POPG (palmitoyl-oleyl-phosphatidylglycerol) (4:1) lipids. We observed that local thinning of the lipid bilayers mediated by the peptide is enhanced in the lipid bilayer containing POPG, consistent with experimental results of selective membrane targeting. The beta-hairpin motif of PG-1 is conserved in both lipid settings, whereas it is highly bent in aqueous solution. The conformational dynamics of PG-1, especially the highly charged beta-hairpin turn region, are found to be mostly responsible for disturbing the membrane. Even though the eventual membrane disruption requires PG-1 oligomers, our simulations clearly show the first step of the monomeric effects. The thinning effects in the bilayer should relate to pore/channel formation in the lipid bilayer and thus be responsible for further defects in the membrane caused by oligomer.
authors.affiliation: Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Woolf
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D003198:Computer Simulation; D008051:Lipid Bilayers / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers; D010455:Peptides; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D011506:Proteins; C094880:protegrin-1; D014867:Water; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine