The effect of cyclization of magainin 2 and melittin analogues on structure, function, and model membrane interactions: Implication to their mode of action

The amphipathic alpha -helical structure is a common motif found in membran e binding polypeptides including cell lytic peptides, antimicrobial peptide s, hormones, and signal sequences. Numerous studies have been undertaken to understand the driving forces for partitioning of amphipathic alpha -helic al peptides into membranes, many of them based on the antimicrobial peptide magainin 2 and the non-cell-selective cytolytic peptide melittin, as parad igms. These studies emphasized the role of linearity in their mode of actio n. Here we synthesized and compared the structure, biological function, and interaction with model membranes of linear and cyclic analogues of these p eptides. Cyclization altered the binding of melittin and magainin analogues to phospholipid membranes. However, at similar bound peptide:lipid molar r atios, both linear and cyclic analogues preserved their high potency to per meate membranes. Furthermore, the cyclic analogues preserved similar to 75% of the helical structure of the linear peptides when bound to membranes. B iological activity studies revealed that the cyclic melittin analogue had i ncreased antibacterial activity but decreased hemolytic activity, whereas t he cyclic magainin 2 analogue had a marked decrease in both antibacterial a nd hemolytic activities. The results indicate that the linearity of the pep tides is not essential for the disruption of the target phospholipid membra ne, but rather provides the means to reach it. In addition, interfering wit h the coil-helix transition by cyclization, while maintaining the same sequ ence of hydrophobic and positively charged amino acids, allows a separated evaluation of the hydrophobic and electrostatic contributions to binding of peptides to membranes.