The self assembly of phospholipid molecules in the bilayer form was considered in terms of equivalent molecular shapes representing intermolecular forces. The equivalent size of each phospholipid headgroup was approximated by the net atomic volume plus the volume of the associated water molecules, which was derived from water/ hydrocarbon partitioning experiments. The equivalent lengths ofunsaturated acyl chains were derived from the retention time data from chromatographic measurements. The spontaneous curvature of various phospholipid monolayers was calculated from their equivalent molecular shapes, and the energy required to flatten them to the bilayer plane was calculated, using the known bending modulus. With increasing bending energy, the mixtures showed increasing susceptibility to phospholipase A2, facilitated lipid tansfer rate by phospholipid exchange proteins, permeability to carboxyfluorescein, incorporation of human erythrocyte proteins, and calcium transport by CaATPase from sarcoplasmic reticulum in reconstituted vesicles. When the calculation was applied to known lipid compositions of nine cellular membranes, the protein/lipid ratio and phospholipid/cholesterol ratio were found to have a positive and a negative correlation, respectively, with the latent bending energy of the phospholipids. The energy expense in conforming to a bilayer phase may be an important physical parameter regarding the activity and the biogenesis of membranes.The regulated diversity in lipid composition of biological membranes is well recognized, but the need for such diversity is not fully understood. Apparently, the lipids in biological membranes do more than provide a passive barrier and a supporting matrix for membrane proteins. There is ample evidence that changes in lipid structure can influence the activity ofmembranes (1). The quest for maintaining a certain "fluidity" fails to explain the diversity of membrane lipid species. It is known that not all lipids found in biological membranes form bilayers when dispersed in water. In fact, a large portion of the membrane lipids do not form bilayers at physiological conditions (pH, calcium concentration, and temperature). These so-called "nonbilayer" lipids generally prefer high curvature structures such as inverted hexagonal (HI,), inverted cubic, and "lipid particles" when dispersed in water (1, 2). However, no such structures have ever been found in functioning biomembranes. It would thus seem that the ability of these lipid mixtures to form high curvature structures upon self assembly, rather than the inverted structures themselves, is needed for the proper functioning of biological membranes.The polymorphism or phase preference of any lipid is governed by the coherence force, which is the combined result of the exclusion volume, polarity, headgroup interactions, and van der Waals interactions between hydrocarbon chains, among others (3, 4). These forces are difficult to account for analytically; therefore the quantitative assessment of the energetics of bilay...