This paper is dedicated to the memory of Professor Elkan Blout. C.M.D. had the privilege of being a post-doctoral associate in Elkan's lab at Harvard Medical School. It was the gift of Elkan that under his mentorship, one not only learned science, but also learned how to be a scientist. Elkan had the knack to recognize the important problems of the day, and see the big picture solutions. And equally important, he set the tone that encouraged each of us to work independently while at the same time enjoying the interchange of the group's ideas. I will always value Elkan's support and development of the young me, and the wonderful interactions I had with him, his wife Gail, and with labmates, over many subsequent years.
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Membrane interactions of designed cationic antimicrobial peptides: The two thresholds†
Article first published online: 8 JAN 2008
DOI: 10.1002/bip.20917
Copyright © 2008 Wiley Periodicals, Inc.
Issue
Biopolymers
Special Issue: This issue is dedicated to the memory of Elkan R. Blout, a founding editor of Biopolymers
Volume 89, Issue 5, pages 360–371, May 2008
Additional Information
How to Cite
Glukhov, E., Burrows, L. L. and Deber, C. M. (2008), Membrane interactions of designed cationic antimicrobial peptides: The two thresholds. Biopolymers, 89: 360–371. doi: 10.1002/bip.20917
- †
Publication History
- Issue published online: 28 FEB 2008
- Article first published online: 8 JAN 2008
- Manuscript Accepted: 17 DEC 2007
- Manuscript Received: 12 NOV 2007
Funded by
- Canadian Institutes of Health Research (CIHR)
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Elsie Winifred Crann Memorial fund
- Abstract
- Article
- References
- Cited By
Keywords:
- antimicrobial peptides;
- peptide-membrane interactions;
- hydrophobicity threshold
Abstract
Novel cationic antimicrobial peptides (CAPs) designed in our lab—typified by sequences such as KKKKKKAAX-AAXAAXAA-NH2, where X = Phe/Trp—display high antibacterial activity but exhibit little or no hemolytic activity towards human red blood cells even at high doses. To clarify the mechanism of their selectivity for bacterial versus mammalian membranes and to increase our understanding of the relationships between primary sequence and bioactivity, a library of derivatives was prepared by increasing segmental hydrophobicity, in which systematic substitutions of Ala for two, three, or four Leu residues were made. Conformationally constrained dimeric and cyclic derivatives were also synthesized. The peptides were examined for activity against pathogenic bacteria (Pseudomonas aeruginosa), hemolytic activity on human red blood cells, and insertion into models of natural bacterial membranes (containing anionic lipids) and mammalian membranes (containing zwitterionic lipids + cholesterol). Results were compared with corresponding properties of the natural CAPs magainin and cecropin. Using circular dichroism and fluorescence spectroscopy, we found that peptide conformation and membrane insertion were sequence dependent, both upon the number of Leu residues, and upon their positions along the hydrophobic core. Membrane disruption was likely enhanced by the fact that the peptides contain potent dimerization-promoting sequence motifs, as assessed by SDS-PAGE gel analysis. The overall results led us to identify distinctions in the mechanism of actions of these CAPs for disruption of bacterial versus mammalian membranes, the latter dependent on surpassing a “second hydrophobicity threshold” for insertion into zwitterionic membranes. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 360–371, 2008.
This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com