2.B.25 The Peptide-mediated Lipid Flip-Flop (PLFF) Family

Hydrophobic peptide-accelerated transleaflet lipid movement (flip-flop) is affected by peptide sequence and vesicle composition and properties (LeBarron and London 2016). Peptides with a completely hydrophobic sequence had no effect on flip-flop. While peptides with a somewhat less hydrophobic sequence accelerated flip-flop, the half-time remained slow (hours) with substantial (0.5mol%) peptide in the membranes. It appears that peptide-accelerated lipid flip-flop involves an event that may reflect a rare state of the peptide or lipid bilayer. There is no simple relationship between peptide overall hydrophobicity and flip-flop, and flip-flop is not closely linked to whether the peptides are in a transmembrane or non-transmembrane (interfacial) inserted state. Flip-flop is not associated with peptide-induced pore formation, but peptide-accelerated flip-flop is initially faster in small (highly curved) unilamellar vesicles than in large unilamellar vesicles. Peptide-accelerated flip-flop is affected by lipid composition, being slowed in vesicles with thick bilayers or those containing 30% cholesterol. Interestingly, these factors also slow spontaneous lipid flip-flop in the absence of peptide. Combined with previous studies, the results are  consistent with acceleration of lipid flip-flop by peptide-induced thinning of bilayer width (LeBarron and London 2016).

There are many peptide phospholipid scramblases, most of which form transmembrane α-helical spanners.  Nakao and Nakano 2022 described and discussed 32 such peptides which fell into three classes:  (1) Hydrophobic peptides, consisting exclusively of hydrophobic residues such asleucine and alanine in the central parts, but may haveother residues at the two ends of the peptides; they form α-helical transmembrane structures but usually have relatively low scramblase activities. (2) the same but containing one or more hydrophilic residues in the centers of these peptides (these usually have greater scramblase activities). The hydrophilic residues in the central parts of the peptides are often two adjacent residies: XW, where X can be any hydrophilic residue (E, K, R, D, Q, N, H, P, Y, S, T) but the two residues can be separated by a helical turn (2 or 3 residues between them, and (3) hydrphobic peptides showing a mismatch between the width of the phospholipid bilayer and the length of the hydrophobic domain of the peptide, causing a discontinuity in the membrane structure. This third type suggests that membrane defects can play roles in flip-flop promotion by transmembane peptides containing central but adjacent, QW, hydrophilic residues (Nakao and Nakano 2022).



LeBarron, J. and E. London. (2016). Effect of lipid composition and amino acid sequence upon transmembrane peptide-accelerated lipid transleaflet diffusion (flip-flop). Biochim. Biophys. Acta. 1858: 1812-1820.

Nakao, H. and M. Nakano. (2022). Flip-Flop Promotion Mechanisms by Model Transmembrane Peptides. Chem Pharm Bull (Tokyo) 70: 519-523.