Structure and mechanism of β-hairpin antimicrobial peptides in lipid bilayers from solid-state NMR spectroscopy

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Abstract
The membrane-bound structure, lipid interaction, and dynamics of the arginine-rich β-hairpin antimicrobial peptide PG-1 as studied by solid-state NMR are highlighted here. A variety of solid-state NMR techniques, including paramagnetic relaxation enhancement, 1H and 19F spin diffusion, dipolar recoupling distance experiments, and 2D anisotropic–isotropic correlation experiments, are used to elucidate the structural basis for the membrane disruptive activity of this representative β-hairpin antimicrobial peptide. We found that PG-1 structure is membrane dependent: in bacteria-mimetic anionic lipid membranes the peptide forms oligomeric transmembrane β-barrels, whereas in cholesterol-rich membranes mimicking eukaryotic cells the peptide forms β-sheet aggregates on the surface of the bilayer. PG-1 causes toroidal pore defects in the anionic membrane, suggesting that the cationic arginine residues drag the lipid phosphate groups along as the peptide inserts. Mutation of PG-1 to reduce the number of cationic residues or to change the arginine guanidinium structure significantly changes the degree of insertion and orientation of the peptide in the lipid membrane, resulting in much weaker antimicrobial activities.