Mode Of Membrane Interaction And Fusogenic Properties Of A De Novo Transmembrane Model Peptide Depend On The Length Of The Hydrophobic Core

Model peptides composed of alanine and leucine residues are often used to mimic
single helical transmembrane domains. Many studies have been carried out to
determine how they interact with membranes. However, few studies have
investigated their lipid-destabilizing effect. We designed three peptides
designated KALRs containing a hydrophobic stretch of 14, 18, or 22
alanines/leucines surrounded by charged amino acids. Molecular modeling
simulations in an implicit membrane model as well as attenuated total
reflection-Fourier transform infrared analyses show that KALR is a good model of
a transmembrane helix. However, tryptophan fluorescence and attenuated total
reflection-Fourier transform infrared spectroscopy indicate that the extent of
binding and insertion into lipids increases with the length of the peptide
hydrophobic core. Although binding can be directly correlated to peptide
hydrophobicity, we show that insertion of peptides into a membrane is determined
by the length of the peptide hydrophobic core. Functional studies were performed
by measuring the ability of peptides to induce lipid mixing and leakage of
liposomes. The data reveal that whereas KALR14 does not destabilize liposomal
membranes, KALR18 and KALR22 induce 40 and 50% of lipid-mixing, and 65 and 80% of
leakage, respectively. These results indicate that a transmembrane model peptide
can induce liposome fusion in vitro if it is long enough. The reasons for the
link between length and fusogenicity are discussed in relation to studies of
transmembrane domains of viral fusion proteins. We propose that fusogenicity
depends not only on peptide insertion but also on the ability of peptides to
destabilize the two leaflets of the liposome membrane.