Molecular modeling of the anandamide-cholesterol complex in the membrane environment.

<p>The anandamide (AEA)-cholesterol complex was generated in vacuo, and subsequently merged with a phosphatidylcholine molecule (PC). The flexible acyl chains of PC could satisfactorily fit with AEA, allowing PC to interact with the AEA-complex. A molecule of sphingomyelin (SM) interacting with cholesterol was added to the system as a representative lipid raft component. The SM-cholesterol complex could also fit with the AEA-cholesterol complex. Namely, in the AEA-cholesterol complex, the α face of cholesterol is fully accessible for the sphingosine chain of SM. This molecular modeling study indicates that AEA can bind to cholesterol in both the PC-rich fluid (Ld) phase and the SM-rich (Lo) phase of the plasma membrane. In particular, the H-bond between cholesterol and AEA is still present after introducing these membrane lipids in the system. The total energy of the system is 180.68 kcal.mol⁻¹ for the cholesterol-sphingosine complex (−14.43 kcal.mol⁻¹ for AEA bound to cholesterol). All models were obtained with the Polak-Ribiere algorithm (for geometry optimization) and then submitted to Monte Carlo simulations.