Correlation between the Free Energy of a Channel-Forming Voltage-Gated Peptide and the Spontaneous Curvature of Bilayer Lipids

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Abstract
The aqueous-membrane partitioning of alamethicin, a voltage-gated channel-forming peptide, was measured as a function of the membrane spontaneous curvature. EPR spectroscopy was used to measure the partitioning of the peptide in lipid compositions formed from dioleoylphosphatidylcholine (DOPC) and varied percentages of dioleoylphosphatidylethanolamine (DOPE), dioleoylphosphatidylethanolamine-N-methyl (DOPE-Me), or dioleoylphosphatidylethanolamine-N,N-dimethyl (DOPE-Me2). When the mole fraction of DOPE in mixtures of DOPC/DOPE is increased the binding of alamethicin decreases, and the increase in binding free energy is found to be linearly dependent upon the mole fraction of DOPE in the mixture. Addition of DOPE-Me or DOPE-Me2 also increases the binding free energy, except that the effect is reduced relative to that of DOPE. The free-energy increase per mole fraction of DOPE was found to be 1400 cal/mol, whereas for DOPE-Me and DOPE-Me2 the free-energy changes were 980 and 630 cal/mol, respectively. When the free-energy changes for alamethicin binding are compared with the previously determined spontaneous curvatures for mixtures of DOPC/DOPE and DOPC/DOPE-Me, the free energy of binding is found to be linearly dependent upon the spontaneous curvature of the bilayer lipids. The effects of membrane lipid unsaturation on the partitioning of alamethicin were also measured and are qualitatively consistent with this conclusion. The sensitivity to spontaneous curvature and the cooperativity that is seen in the binding curves for alamethicin are postulated to be a result of a localized thinning of the bilayer promoted by this peptide.