Structure, location, and lipid perturbations of melittin at the membrane interface

Melittin is arguably the most widely studied amphipathic, membrane-lytic a- helical peptide. Although several lines of evidence suggest an interfacial membrane location at low concentrations, melittin's exact position and dept h of penetration into the hydrocarbon core are unknown. Furthermore, the st ructural basis for its lytic action remains largely a matter of conjecture. Using a novel x-ray absolute-scale refinement method, we have now determin ed the location, orientation, and likely conformation of monomeric melittin in oriented phosphocholine lipid multilayers. Its helical axis is aligned parallel to the bilayer plane at the depth of the glycerol groups, but its average conformation differs from the crystallographic structure. As observ ed earlier for another amphipathic alpha -helical peptide, the lipid pertur bations induced by melittin are remarkably modest. Small bilayer perturbati ons thus appear to be a general feature of amphipathic helices at low conce ntrations. In contrast, a dimeric form of melittin causes larger structural perturbations under otherwise identical conditions. These results provide direct structural evidence that self-association of amphipathic helices may be the crucial initial step toward membrane lysis.