Structure Activity Relationship for a Synergistic Pair of Antimicrobial Peptides from the Magainin Family

Abstract

The antimicrobial peptides Magainin 2 (Mag2) and PGLa are both found in the skin of the African frog Xenopus laevis. They show high antimicrobial activity against bacteria, fungi, and cancer cells.[1] Both peptides form amphipathic α-helices upon binding to a lipid bilayer. Previous studies revealed that mixtures of Mag2 and PGLa show synergistic effects,[2] and the formation of stable 1:1 heterodimeric peptide pores has been proposed as a possible mechanism.The membrane alignment of each of these two peptides per se has been determined with high accuracy using solid state 2H-, 15N-, and 19F-NMR spectroscopy. Using solid state 2H-NMR, we have previously characterized the orientation of PGLa on its own and in the presence of an equimolar amount of Mag2, and found an inserted transmembrane orientation of PGLa in DMPC/DMPG only in the presence of Mag2.[3] On the other hand, Mag2 always stays flat on the surface of the lipid bilayer, both on its own and in the presence of PGLa.The aim of the present study was to determine the detailed local interaction between the two peptides in the membrane-bound state, taking hydrophobic and charge interactions into account. Several mutations were introduced at potentially crucial positions of either peptide and investigated by 15N-NMR and biological assays. It was found that synergy is correlated with the insertion of PGLa, and important residues for synergy could thus be identified.