Influence of Head Group Mismatch on the Miscibility of Phospholipids in the Physiologically-Relevant Fluid Phase:  A Nearest-Neighbor Recognition Analysis

The mixing behavior of phosphoethanolamine (PE)-like and phosphoglycerol (PG)-like lipids have been examined in the fluid bilayer state by use of nearest-neighbor recognition methods [Vigmond, S. J.; Dewa, T.; Regen, S. L. J. Am. Chem. Soc . 1995, 117, 7838]. Disulfide-based phospholipid dimers derived from 1,2-dimyristoyl- sn -glycero-3-phosphoethanolamine (DMPE) have been synthesized, containing PE- and PG-like head groups. Subsequent exchange and equilibration of the monomer units, via thiolate−disulfide interchange, produced a nonstatistical distribution of dimers in the fluid bilayer phase (60 °C); i.e., a heterodimer/homodimer ratio of 1.76 ± 0.05 was formed. Analogous membranes that were rich in cholesterol (i.e., 29 mol %) produced a statistical mixture of dimers. Equilibration experiments that were carried out using PE-like and PG-like lipids derived from 1,2-dipalmitoyl- sn -glycero-3-phosphoethanolamine (DPPE) and DMPE, respectively, gave similar results, except that a greater level of nearest-neighbor recognition was evident in the absence of cholesterol. The biological implications of these findings are briefly discussed.