STUDIES OF THE THERMOTROPIC PHASE-BEHAVIOR OF PHOSPHATIDYLCHOLINES CONTAINING 2-ALKYL SUBSTITUTED FATTY ACYL CHAINS - A NEW CLASS OF PHOSPHATIDYLCHOLINES FORMING INVERTED NONLAMELLAR PHASES

We have synthesized a number of 1,2-diacyl phosphatidylcholines with h ydrophobic substituents adjacent to the carbonyl group of the fatty ac yl chain and studied their thermotropic phase behavior by differential scanning calorimetry, P-31-nuclear magnetic resonance spectroscopy, a nd x-ray diffraction. Our results indicate that the hydrocarbon chain- melting phase transition temperatures of these lipids are lower than t hose of the n-saturated diacylphosphatidylcholines of similar chain le ngth. In the gel phase, the 2-alkyl substituents on the fatty acyl cha ins seem to inhibit the formation of tightly packed, partially dehydra ted, quasicrystalline bilayers (L(c) phases), although possibly promot ing the formation of chain-interdigitated bilayers. In the liquid-crys talline state, however, these 2-alkyl substituents destabilize the lam ellar phase with respect to one or more inverted nonlamellar structure s. In general, increases in the length, bulk, or rigidity of the alkyl substituent result in an increased destabilization of the lamellar ge l and liquid-crystalline phases and a greater tendency to form inverte d nonlamellar phases, the nature of which depends upon the size of the 2-alkyl substituent. Unlike normal non-lamella-forming lipids such as the phosphatidylethanolamines, increases in the length of the main ac yl chain stabilize the lamellar phases and reduce the tendency to form nonlamellar structures. Our results establish that with a judicious c hoice of a 2-alkyl substituent and hydrocarbon chain length, phosphati dylcholines (and probably most other so-called ''bilayer-preferring'' lipids) can be induced to form a range of inverted nonlamellar structu res at relatively low temperatures. The ability to vary the lamellar/n onlamellar phase preference of such lipids should be useful in studies of bilayer/nonbilayer phase transitions and of the molecular organiza tion of various nonlamellar phases. Moreover, because the nonlamellar phases can easily be induced at physiologically relevant temperatures and hydration levels while avoiding changes in polar headgroup composi tion, this new class of 2-alkyl-substituted phosphatidylcholines shoul d prove valuable in studies of the physiological role of non-lamella-f orming lipids in reconstituted lipid-protein model membranes.