Membrane-disruptive abilities of β-hairpin antimicrobial peptides correlate with conformation and activity: A 31P and 1H NMR study

The membrane interaction and solution conformation of two mutants of the β-hairpin antimicrobial peptide, protegrin-1 (PG-1), are investigated to understand the structural determinants of antimicrobial potency. One mutant, [A6,8,13,15] PG-1, does not have the two disulfide bonds in wild-type PG-1, while the other, [Δ4,18 G10] PG-1, has only half the number of cationic residues. 31P solid-state NMR lineshapes of uniaxially aligned membranes indicate that the membrane disorder induced by the three peptides decreases in the order of PG-1>[Δ4,18 G10] PG-1≫[A6,8,13,15] PG-1. Solution NMR studies of the two mutant peptides indicate that [Δ4,18 G10] PG-1 preserves the β-hairpin fold of the wild-type peptide while [A6,8,13,15] PG-1 adopts a random coil conformation. These NMR results correlate well with the known activities of these peptides. Thus, for this class of peptides, the presence of a β-hairpin fold is more essential than the number of cationic charges for antimicrobial activity. This study indicates that 31P NMR lineshapes of uniaxially aligned membranes are well correlated with antimicrobial activity, and can be used as a diagnostic tool to understand the peptide-lipid interactions of these antimicrobial peptides.