Interaction of Short Pentavalent Cationic Peptides with Negatively Charged DPPG Monolayers and Bilayers: Influence of Peptide Modifications on Binding.

The binding of oligopeptides with the structure (RX)4R and (KXX)4K, with X being the amino acid G or A, to lipid monolayers and bilayers of dipalmitoyl-phosphatidylglycerol (DPPG) was studied and compared to the binding effects of peptides with the structure (KX)4K. The monolayer adsorption experiments again showed the superposition of condensation effects due to charge compensation and insertion of amino acid side chains leading to expansion of the monolayer. The latter effect was enhanced when glycine was replaced by alanine. The thermotropic phase behavior of dipalmitoyl-phosphatidylglycerol (DPPG) bilayer membranes and their mixtures with short cationic model peptides was investigated by differential scanning calorimetry and infrared spectroscopy. Increasing the charge distance of the lysine residues in the series (K)5, (KG)4K, and (KGG)4K results in an upshift of the main phase transition of DPPG up to 5 K, as predicted for pure electrostatic binding. All peptides exhibit only unordered structures in bulk solution as well as when bound to DPPG bilayers. (KGG)4K additionally shows a high propensity of turn structures due to its flexibility. The exchange of glycine by alanine in (KAA)4K leads only to a marginal increase in Tm, in contrast to the binding of (KA)4K where the formation of intervesicular antiparallel β-sheets occurs, leading to a much more pronounced stabilization of the gel phase. This shows that the sequence and flexibility of the oligopeptides has an important influence on the formation of secondary structures bound to the bilayers. Binding of (RX)4R peptides to DPPG bilayers has almost no influence on the lipid phase transition in bilayers. Here, condensation and insertion effects almost compensate, as the results of monolayer experiments show. This is due to the higher propensity of arginine side chains to insert into the lipid headgroup region.