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The Gaussian Curvature Elastic Modulus of N-Monomethylated Dioleoylphosphatidylethanolamine: Relevance to Membrane Fusion and Lipid Phase Behavior

D. P. Siegel ^* and M. M. Kozlov 

^* Givaudan, Cincinnati, Ohio; and Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Tel Aviv, Israel

Correspondence: Address reprint requests to David Paul Siegel, Givaudan, Inc., 1199 Edison Dr., Cincinnati, OH 45216. Tel.: 513-948-4840; E-mail: david.siegel{at}givaudan.com.

The energy of intermediates in fusion of phospholipid bilayers is sensitive to the saddle splay (Gaussian curvature) elastic modulus of the lipid monolayers. The value is also important in understanding the stability of inverted cubic (Q_II) and rhombohedral (R) phases relative to the lamellar (L) and inverted hexagonal (H_II) phases in phospholipids. However, cannot be measured directly. It was previously measured by observing changes in Q_II phase lattice dimensions as a function of water content. Here we use observations of the phase behavior of N-mono-methylated dioleoylphosphatidylethanolamine (DOPE-Me) to determine At the temperature of the L/Q_II phase transition, T_Q, the partial energies of the two phases are equal, and we can express in terms of known lipid monolayer parameters: the spontaneous curvature of DOPE-Me, the monolayer bending modulus _m, and the distance of the monolayer neutral surface from the bilayer midplane, . The calculated ratio is –0.83 ± 0.08 at T_Q 55°C. The uncertainty is due primarily to uncertainty in the value of for the L phase. This value of is in accord with theoretical expectations, including recent estimates of the value required to rationalize observations of rhombohedral (R) phase stability in phospholipids. The value substantially affects the free energy of formation of fusion intermediates: more energy (tens of k_BT) is required to form stalks and fusion pores (ILAs) than estimated solely on the basis of the bending elastic energy. In particular, ILAs are much higher in energy than previously estimated. This rationalizes the action of fusion-catalyzing proteins in stabilizing nascent fusion pores in biomembranes; a function inferred from recent experiments in viral systems. These results change predictions of earlier work on ILA and Q_II phase stability and L/Q_II phase transition mechanisms. To our knowledge, this is the first determination of the saddle splay (Gaussian) modulus in a lipid system consisting only of phospholipids.

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