The phase behavior of dioleoylphosphatidylethanolamine in aqueous solutions of urea, N,N'-dimethylurea (DMU), and N,N,N',N'-tetramethylurea (TMU) has been characterized by synchrotron X-ray diffraction and differential scanning calorimetry. All three solutes stabilize the lamellar liquid-crystalline phase at the expense of lamellar-gel phase and inverted hexagonal phase of the phospholipid when present in concentrations up to 3 M. X-ray diffraction data demonstrated that the repeat spacing of DOPE increased with increasing urea concentration, but decreased as the DMU and TMU concentrations increased. The repeat spacing of DOPE in the liquid-crystal phase dispersed in the three solutes is d(urea)>d(DMU)>d(TMU). The molecular mechanisms underlying these observations are discussed in terms of either membrane Hofmeister effect, where urea acts as a water structure breaker, or a direct insertion effect of the amphiphilic DMU and TMU molecules into the lipid head groups in the interfacial region of the phospholipid bilayer.
