Hydrophobic alkyl headgroups strongly promote membrane curvature and violate the headgroup volume correlation due to "headgroup" insertion.

The ability of lipid aggregates to form planar bilayers, rather than highly curved micellar or inverted structures, is dependent on the relative geometries of the headgroup and hydrocarbon regions. The headgroup volume approach to lipid structure provided a quantitative link between a lipid's headgroup size and its ability to promote curved, inverted hexagonal (H-II) structures in a phosphatidylethanolamine (PtdEtn) matrix [Lee et al. (1993) Biophys. J. 65, 1429-1432]. Phosphatidylalkanols (PtdAlks) are shown here to promote curvature with a potency that far exceeds and a chain length dependence contrary to the expectations of the headgroup volume approach, suggestive of an atypical alkyl "headgroup" conformation. A homologous series of 3-substituted triacylglycerols (TAGs), for which 3-acyl "headgroup" insertion is established, exhibits a chain length dependence similar to the PtdAlks, evidence that the deviation is of common origin. The potency of the TAGs to promote curvature is unprecedented, and the onset of saturation, which parallels the dramatic promotion of curvature, occurs at mole fractions as low as 0.0025. The potency of the PtdAlks or TAGs to promote curvature exceeds that of all mammalian phospholipids examined. Thermodynamic analysis implicates the enthalpic curvature stress imparted upon the membrane matrix as the dominant energetic factor. The imparted stress ranges from -930 J mol(-1) for phosphatidylcholine to +7.5 kJ mol(-1) for 3-palmitoyl TAG. The results affirm the geometric considerations of membrane structure and indicate that alkyl headgroups tend to insert into the bilayer and increase the enthalpic curvature stress within the membrane.