Structural characterization of de novo designed L5K5W model peptide isomers with potent antimicrobial and varied hemolytic activities.
In an effort to develop short antimicrobial peptides with simple amino acid compositions, we generated a series of undecapeptide isomers having the L(5)K(5)W formula. Amino acid sequences were designed to be perfectly amphipathic when folded into a helical conformation by converging leucines onto one side and lysines onto the other side of the helical axis. The single tryptophans, whose positions were varied in the primary structures, were located commonly at the critical amphipathic interface in the helical wheel projection. Helical conformations and the tryptophanyl environments of the 11 L(5)K(5)W peptides were confirmed and characterized by circular dichroism, fluorescence and nuclear magnetic resonance spectroscopy. All of the isomers exhibited a potent, broad-spectrum of antibacterial activity with just a slight variance in individual potency, whereas their hemolytic activities against human erythrocytes were significantly diversified. Interestingly, helical dispositions and fluorescence blue shifts of the peptides in aqueous trifluoroethanol solutions, rather than in detergent micelles, showed a marked linear correlation with their hemolytic potency. These results demonstrate that our de novo design strategy for amphipathic helical model peptides is effective for developing novel antimicrobial peptides and their hemolytic activities can be estimated in correlation with structural parameters.
Department of Biotechnology, Research Institute for Biomedical and Health Science, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk 380-701, Korea.
Seo-Jin
SJ
Kim
Jae-Seok
JS
Kim
Yoo-Sup
YS
Lee
Dae-Won
DW
Sim
Sung-Hee
SH
Lee
Young-Yil
YY
Bahk
Kwang-Ho
KH
Lee
Eun-Hee
EH
Kim
Sung-Jean
SJ
Park
Bong-Jin
BJ
Lee
Hyung-Sik
HS
Won
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology; D002463:Cell Membrane Permeability; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects; D053878:Hemolytic Agents / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D053878:Hemolytic Agents; D009842:Oligopeptides; D014364:Tryptophan