A synergistic enhancement of activities has been described for the amphipathic cationic antimicrobial peptides magainin 2 and PGLa when tested in antimicrobial assays or in biophysical experiments using model membranes. In the presence of magainin 2, PGLa changes from an in-planar alignment parallel to the membrane surface to a more transmembrane orientation when investigated in membranes made from fully saturated PC or PC/PG, but not when one of the fatty acyl chains is unsaturated. Such lipid-mediated changes in the membrane topology of polypeptide domains could provide an interesting mechanism for the regulation of membrane proteins. Here we investigated the PGLa topology in a wide variety of membranes made of saturated or unsaturated PE, PC, and/or PG using 15N solid-state NMR spectroscopy. In contrast to predictions made by previous models the data show that membrane curvature has only a minor effect on PGLa realignment. Furthermore, using 2H solid-state NMR spectroscopy of deuterated phospholipid fatty acyl chains the order parameters of the lipids were investigated in the presence of PGLa, magainin, or equimolar peptide mixtures. Both peptides cause a pronounced decrease in the order parameters when oriented parallel to the membrane surface, an effect that reverts when PGLa flips into transmembrane alignments. Taken together, these data are suggestive that the magainin-induced disordering of fatty acyl chains provides an important driving force for PGLa realignment.