title: Designed beta-boomerang antiendotoxic and antimicrobial peptides: structures and activities in lipopolysaccharide.
abstract: Lipopolysaccharide (LPS), an integral part of the outer membrane of Gram-negative bacteria, is involved in a variety of biological processes including inflammation, septic shock, and resistance to host-defense molecules. LPS also provides an environment for folding of outer membrane proteins. In this work, we describe the structure-activity correlation of a series of 12-residue peptides in LPS. NMR structures of the peptides derived in complex with LPS reveal boomerang-like beta-strand conformations that are stabilized by intimate packing between the two aromatic residues located at the 4 and 9 positions. This structural feature renders these peptides with a high ability to neutralize endotoxicity, >80% at 10 nM concentration, of LPS. Replacements of these aromatic residues either with Ala or with Leu destabilizes the boomerang structure with the concomitant loss of antiendotoxic and antimicrobial activities. Furthermore, the aromatic packing stabilizing the beta-boomerang structure in LPS is found to be maintained even in a truncated octapeptide, defining a structured LPS binding motif. The mode of action of the active designed peptides correlates well with their ability to perturb LPS micelle structures. Fourier transform infrared spectroscopy studies of the peptides delineate beta-type conformations and immobilization of phosphate head groups of LPS. Trp fluorescence studies demonstrated selective interactions with LPS and the depth of insertion into the LPS bilayer. Our results demonstrate the requirement of LPS-specific structures of peptides for endotoxin neutralizations. In addition, we propose that structures of these peptides may be employed to design proteins for the outer membrane.
authors.affiliation: School of Biological Sciences, Division of Structural and Computational Biology, Nanyang Technological University, Singapore 637551.
authors.forename: Anirban
authors.initials: A
authors.lastname: Bhunia
authors.affiliation: School of Biological Sciences, Division of Structural and Computational Biology, Nanyang Technological University, Singapore 637551.
authors.forename: Harini
authors.initials: H
authors.lastname: Mohanram
authors.affiliation: School of Biological Sciences, Division of Structural and Computational Biology, Nanyang Technological University, Singapore 637551.
authors.forename: Prerna N
authors.initials: PN
authors.lastname: Domadia
authors.affiliation: School of Biological Sciences, Division of Structural and Computational Biology, Nanyang Technological University, Singapore 637551.
authors.forename: Jaume
authors.initials: J
authors.lastname: Torres
authors.affiliation: School of Biological Sciences, Division of Structural and Computational Biology, Nanyang Technological University, Singapore 637551.
authors.forename: Surajit
authors.initials: S
authors.lastname: Bhattacharjya
mesh_terms: D020816:Amino Acid Motifs; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D004731:Endotoxins / Q000737:chemistry*; D006388:Hemagglutinins / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry; D008070:Lipopolysaccharides / Q000737:chemistry*; D008823:Micelles; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence / Q000379:methods; D013055:Spectrophotometry, Infrared / Q000379:methods
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D004731:Endotoxins; D006388:Hemagglutinins; D008051:Lipid Bilayers; D008070:Lipopolysaccharides; D008823:Micelles; D010455:Peptides