Cholesterol-Phospholipid Association in Fluid Bilayers: A Thermodynamic Analysis from Nearest-Neighbor Recognition Measurements

The mixing behavior of exchangeable, disulfide-based mimics of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol has been examined as a function of temperature in host membranes made from DPPC and cholesterol in the liquid-disordered phase (ld), in the liquid-ordered phase (lo), and in the liquid-disordered/liquid-ordered coexistence region (ld/lo). In the ld region, lipid mixing was found to be temperature insensitive, reflecting close to ideal behavior. In contrast, a significant temperature dependence was observed in the lo phase from 45 to 60°C, when 35 or 40 mol % sterol was present. In this region, sterol-phospholipid association was characterized by ΔHo = −2.06 ± 0.14 kcal/mol of phospholipid and ΔS° = −4.48 ± 0.44 cal/K mol of phospholipid. From 60 to 65°C, the mixing of these lipids was found to be insensitive to temperature, and sterol-phospholipid association was now entropy driven; that is, ΔHo = −0.23 ± 0.38 kcal/mol of phospholipid and ΔS° = +1.68 ± 1.12 cal/K mol of phospholipid. In the liquid-disordered/liquid-ordered coexistence region, changes in lipid mixing reflect changes in the phase composition of the membrane.