Net Interactions That Push Cholesterol Away from Unsaturated Phospholipids Are Driven by Enthalpy

The exchangeable unsaturated phospholipids c1-Phos and c3-Phos, which bear one and three permanent kinks in their acyl chains, are mimics of the biologically important, low-melting phosphatidylcholines (PC) having one and three cis double bonds in their sn-2 chains (i.e., 16:0,18:1 PC and 16:0,18:3 PC, respectively. The net interaction between an exchangeable form of cholesterol (Chol) with c1-Phos and with c3-Phos has been investigated using the nearest-neighbor recognition method. These interactions were found to be unfavorable in both cases having a positive free energy, ω, for replacing like by unlike nearest-neighbor contacts. The values for this free energy (or interaction parameter) were ω = +165 cal/mol between Chol and c1-Phos, and ω = +395 cal/mol between Chol and c3-Phos. We now report the temperature dependence of these interactions in liquid-disordered bilayers. Their experimentally determined temperature dependencies, in combination with Monte Carlo simulations, revealed that the interaction...