Molecular basis for endotoxin neutralization by amphipathic peptides derived from the alpha-helical cationic core-region of NK-lysin.
An analysis of the interaction of the NK-lysin derived peptide NK-2 and of analogs thereof with bacterial lipopolysaccharide (LPS, endotoxin) was performed to determine the most important biophysical parameters for an effective LPS neutralization. We used microcalorimetry, FTIR spectroscopy, Zeta potential measurements, and small-angle X-ray scattering to analyze the peptide:LPS binding enthalpy, the accessible LPS surface charge, the fluidity of the LPS hydrocarbon chains, their phase transition enthalpy change, the aggregate structure of LPS, and how these parameters are modulated by the peptides. We conclude that (i) a high peptide:LPS binding affinity, which is facilitated by electrostatic and hydrophobic interactions and which leads to a positive Zeta potential, (ii) the formation of peptide-enriched domains, which destabilize the lipid packing, demonstrated by a drastic decrease of phase transition enthalpy change of LPS, and (iii) the multilamellarization of the LPS aggregate structure are crucial for an effective endotoxin neutralization by cationic peptides.
Brandenburg
Klaus
K
Division of Biophysics, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
Garidel
Patrick
P
Fukuoka
Satoshi
S
Howe
Jörg
J
Koch
Michel H J
MH
Gutsmann
Thomas
T
Andrä
Jörg
J
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D044367:Phase Transition; D011510:Proteolipids / Q000737:chemistry; D019779:Salmonella enterica / Q000276:immunology; D053838:Scattering, Small Angle; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
D000900:Anti-Bacterial Agents; D004731:Endotoxins; C093238:NK-lysin; D010455:Peptides; D011510:Proteolipids; C475945:peptide NK-2