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Melittin-Induced Bilayer Leakage Depends on Lipid Material Properties: Evidence for Toroidal Pores

Daniel Allende ^* , S. A. Simon  and Thomas J. McIntosh ^*

Departments of ^* Cell Biology and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710

Correspondence: Address reprint requrests to Thomas J. McIntosh, E-Mail: t.mcintosh{at}cellbio.duke.edu.

The membrane-lytic peptide melittin has previously been shown to form pores in lipid bilayers that have been described in terms of two different structural models. In the "barrel stave" model the bilayer remains more or less flat, with the peptides penetrating across the bilayer hydrocarbon region and aggregating to form a pore, whereas in the "toroidal pore" melittin induces defects in the bilayer such that the bilayer bends sharply inward to form a pore lined by both peptides and lipid headgroups. Here we test these models by measuring both the free energy of melittin transfer (G°) and melittin-induced leakage as a function of bilayer elastic (material) properties that determine the energetics of bilayer bending, including the area compressibility modulus (K_a), bilayer bending modulus (k_c), and monolayer spontaneous curvature (R_o). The addition of cholesterol to phosphatidylcholine (PC) bilayers, which increases K_a and k_c, decreases both G° and the melittin-induced vesicle leakage. In contrast, the addition to PC bilayers of molecules with either positive R_o, such as lysoPC, or negative R_o, such as dioleoylglycerol, has little effect on G°, but produces large changes in melittin-induced leakage, from 86% for 8:2 PC/lysoPC to 18% for 8:2 PC/dioleoylglycerol. We observe linear relationships between melittin-induced leakage and both K_a and However, in contrast to what would be expected for a barrel stave model, there is no correlation between observed leakage and bilayer hydrocarbon thickness. All of these results demonstrate the importance of bilayer material properties on melittin-induced leakage and indicate that the melittin-induced pores are defects in the bilayer lined in part by lipid molecules.

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