Mechanism of Action of β-Hairpin Antimicrobial Peptides

Abstract

Previous work showed that the β-hairpin antimicrobial peptide (AMP) protegrin forms stable octameric β-barrels and tetrameric arcs (half barrels) in both implicit and explicit membranes. Here, we extend this investigation to several AMPs of similar structure: tachyplesin, androctonin, polyphemusin, gomesin, and the retrocyclin θ-defensin. We also examine synthetic β-sheet peptides selected from a combinatorial library for their ability or inability to form pores in lipid membranes. When heptameric, octameric, and decameric β-barrels and tetrameric arcs of these peptides were initially embedded in preformed neutral and anionic lipid pores, a variety of behaviors and membrane binding energies were observed. The synthetic peptides bound very strongly and formed stable barrels and arcs in both neutral and anionic pores. The natural AMPs exhibited unfavorable or marginally favorable binding energy and kinetic stability in neutral pores, consistent with the lower hemolytic activity of some of them compared with protegrin. Binding to anionic pores was more favorable, but significant distortions of the barrel or arc structures were sometimes noted. These results are discussed in light of the available experimental data. The diversity of behaviors obtained makes it unlikely that the barrel and arc mechanisms are valid for the entire family of β-hairpin AMPs.