Cyclotide-membrane interactions: Defining factors of membrane binding, depletion and disruption

► Prototypic cyclotides bind to and disrupt lipid membranes. ► The bracelet cyclotide cycloviolacin O2 is more potent than the Möbius kalata B1 and B2. ► Potency is dependent on electrostatics and on cyclotide secondary and tertiary structure. ► A conserved glutamic acid has a key role for PE-lipid specific extraction. ► A 100-fold difference in bacteria to human model membrane selectivity was observed.