Queensland University of Technology
Is the Mirror Image a True Reflection? Challenging the Chirality Paradigm in Peptide-lipid Interactions
Peptide-lipid interactions are assumed to be independent of peptide chirality, probably because it is often ignored that lipid membranes are chiral. Thus, native and mirror image forms of peptides that act by binding to lipid are expected to have identical biological activities. Cyclotides, membrane-active peptides expressed in plants with specificity for phosphatidylethanolamine (PE)-phospholipids, challenge this paradigm: kalata B1, the prototypic cyclotide, is more active than its mirror image.
Membrane chirality results from one chiral centre within the glycerol moiety of phospholipids; thus, to investigate whether the membrane chirality explains differences between native kalata B1 and its enantiomer, we synthesised phospholipids with non-natural chirality. We demonstrated that mirror image forms of kalata B1 prefer to bind to membranes of the same chirality.
This study shows that the chiral environment of lipid bilayers can modulate the function of membrane-active peptides and challenges the view that peptide-lipid interactions are independent of membrane chirality.