Roles of Hydrophobicity and Charge Distribution of Cationic Antimicrobial Peptides in Peptide-Membrane Interactions
Top Cited Papers
Open Access
- 1 March 2012
- journal article
- Published by Elsevier BV
- Vol. 287 (10), 7738-7745
- https://doi.org/10.1074/jbc.m111.303602
Abstract
Cationic antimicrobial peptides (CAPs) occur as important innate immunity agents in many organisms, including humans, and offer a viable alternative to conventional antibiotics, as they physically disrupt the bacterial membranes, leading to membrane lysis and eventually cell death. In this work, we studied the biophysical and microbiological characteristics of designed CAPs varying in hydrophobicity levels and charge distributions by a variety of biophysical and biochemical approaches, including in-tandem atomic force microscopy, attenuated total reflection-FTIR, CD spectroscopy, and SDS-PAGE. Peptide structural properties were correlated with their membrane-disruptive abilities and antimicrobial activities. In bacterial lipid model membranes, a time-dependent increase in aggregated β-strand-type structure in CAPs with relatively high hydrophobicity (such as KKKKKKALFALWLAFLA-NH(2)) was essentially absent in CAPs with lower hydrophobicity (such as KKKKKKAAFAAWAAFAA-NH(2)). Redistribution of positive charges by placing three Lys residues at both termini while maintaining identical sequences minimized self-aggregation above the dimer level. Peptides containing four Leu residues were destructive to mammalian model membranes, whereas those with corresponding Ala residues were not. This finding was mirrored in hemolysis studies in human erythrocytes, where Ala-only peptides displayed virtually no hemolysis up to 320 μM, but the four-Leu peptides induced 40-80% hemolysis at the same concentration range. All peptides studied displayed strong antimicrobial activity against Pseudomonas aeruginosa (minimum inhibitory concentrations of 4-32 μM). The overall findings suggest optimum routes to balancing peptide hydrophobicity and charge distribution that allow efficient penetration and disruption of the bacterial membranes without damage to mammalian (host) membranes.Keywords
This publication has 38 references indexed in Scilit:
- Correlation of Charge, Hydrophobicity, and Structure with Antimicrobial Activity of S1 and MIRIAM PeptidesBiochemistry, 2010
- Tracking Molecular Interactions in Membranes by Simultaneous ATR-FTIR-AFMBiophysical Journal, 2009
- Detergent binding explains anomalous SDS-PAGE migration of membrane proteinsProceedings of the National Academy of Sciences of the United States of America, 2009
- Infrared Study of the Effect of Hydration on the Amide I Band and Aggregation Properties of Helical PeptidesThe Journal of Physical Chemistry B, 2007
- Role of Peptide Hydrophobicity in the Mechanism of Action of α-Helical Antimicrobial PeptidesAntimicrobial Agents and Chemotherapy, 2007
- Motifs of Two Small Residues can Assist but are not Sufficient to Mediate Transmembrane Helix InteractionsJournal of Molecular Biology, 2004
- Antimicrobial peptides of multicellular organismsNature, 2002
- Guidelines for membrane protein engineering derived from de novo designed model peptidesPeptide Science, 1998
- Mode of action of linear amphipathic α-helical antimicrobial peptidesPeptide Science, 1998
- Anionic Phospholipids Modulate Peptide Insertion into MembranesBiochemistry, 1997