PEPTIDE HYDROPHOBICITY CONTROLS THE ACTIVITY AND SELECTIVITY OF MAGAININ-2 AMIDE IN INTERACTION WITH MEMBRANES

The magainins are antibacterial peptides from the skin of Xenopus laev is. They show a broad range of activity against prokaryotic cells but lyse eukaryotic cells poorly. To elucidate the influence of peptide hy drophobicity on membrane activity and selectivity, we designed and syn thesized analogs of magainin 2 amide with slightly varying hydrophobic ities but retained hydrophobic moment, peptide charge, and angle subte nded by the hydrophilic helix region. Circular dichroism investigation s of the peptides revealed that all peptides investigated adopt an cl- helical conformation when bound to phospholipid vesicles. Dye-releasin g experiments from vesicles of phosphatidylglycerol (PG) showed that t he membrane-permeabilizing activity of the analogs is not influenced b y peptide hydrophobicity. In contrast, the permeability-enhancing acti vity on vesicles bearing high amounts of phosphatidylcholine (PC) incr eases drastically with enhanced peptide hydrophobicity, resulting in a reduced selectivity of more hydrophobic analogs for negatively charge d membranes. Likewise, the peptide affinity to PC-rich membranes incre ases in the order of hydrophobicity. Correlation of peptide binding an d membrane permeabilization of PC/PG (3:1) vesicles revealed that the observed differences in peptide activity on membranes of low negative surface charge are mainly caused by the different binding affinities. The antibacterial and hemolytic activity of the peptides increases wit h enhanced hydrophobicity. A strong correlation was found between the hemolytic effect and the bilayer-permeabilizing activity against PC-ri ch vesicles. Whereas the antibacterial specificity of the more hydroph obic analogs is retained for Escherichia coli, the specificity for Pse udomonas aeruginosa decreases with increasing hydrophobicity.