Mechanisms of the interaction of α-helical transmembrane peptides with phospholipid bilayers

The synthetic peptide acetyl-K2-G-L24-K2-A-amide (P24) and its analogs have been successfully utilized as models of the hydrophobic transmembrane α-helical segments of integral membrane proteins. The central polyleucine region of these peptides was designed to form a maximally stable, very hydrophobic α-helix which will partition strongly into the hydrophobic environment of the lipid bilayer core, while the dilysine caps were designed to anchor the ends of these peptides to the polar surface of the lipid bilayer and to inhibit the lateral aggregation of these peptides. Moreover, the normally positively charged N-terminus and the negatively charged C-terminus have both been blocked in order to provide a symmetrical tetracationic peptide, which will more faithfully mimic the transbilayer region of natural membrane proteins and preclude favorable electrostatic interactions. In fact, P24 adopts a very stable α-helical conformation and transbilayer orientation in lipid model membranes. The results of our recent studies of the interaction of this family of α-helical transmembrane peptides with phospholipid bilayers are summarized here.