Lipid dependence of membrane anchoring properties and snorkeling behavior of aromatic and charged residues in transmembrane peptides.

31P NMR spectroscopy was used to investigate the effects of transmembrane alpha-helical peptides with different flanking residues on the phase behavior of phosphatidylethanolamine and phosphatidylethanolamine/phosphatidylglycerol (molar ratio 7:3) model membranes. It was found that tryptophan-flanked (WALP) peptides and lysine-flanked (KALP) peptides both promote formation of nonlamellar phases in these lipid systems in a mismatch-dependent manner. Based on this mismatch dependence, it was concluded that the effective hydrophobic length of KALP peptides is considerably shorter than that of the corresponding WALP peptides. Peptides with other positively charged residues showed very similar effects as KALP. The results suggest that the peptides have a well-defined effective hydrophobic length, which is different for charged and aromatic flanking residues, but which is independent of the precise chemical nature of the side chain. Strikingly, the effective length of KALP peptides in the lipid systems investigated here is much smaller than that previously found for the same peptides in phosphatidylcholine. This suggests that snorkeling of lysine side chains, as proposed to occur in phosphatidylcholine, does not occur in lipid systems that are prone to form nonlamellar phases by themselves. This suggestion was supported by using peptides with shortened lysine side chains and by investigating the effects of mixtures of WALP and KALP peptides. The lipid dependency of the snorkeling behavior is explained by considering the free energy cost of snorkeling in relation to the free energy cost of the formation of nonlamellar phases.