A coarse-grained molecular dynamics investigation of the phase behavior of DPPC/cholesterol mixtures

• Phase coexistence diagram of the DPPC/cholesterol bilayers using the MARTINI model.
• A Voronoi tessellation approach is employed to identify coexisting phases.
• The model predicts gel/Lo coexistence, while the Lo/Ld/ transition is continuous.
• The lipid molecules dynamics feature a subdiffusive regime at short times t<100 ns.
• Activation energies for normal diffusion show good agreement with experiments.

We report a systematic molecular dynamics computer simulation investigation of the phase behavior of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/cholesterol (CHOL) bilayers for a wide range of temperatures and cholesterol compositions (0–50%). Our simulations consist of several thousand phospholipids modeled with the coarse grained MARTINI forcefield covering timescales of tens of microseconds. We employ Voronoi and Delaunay constructions to quantify local compositions in an attempt to identify coexistence regions with the liquid ordered (Lo) phase. We combine this analysis with the chain order parameter and in plane pair correlation functions and propose a phase coexistence diagram for the DPPC/CHOL mixture. We find stable liquid ordered phases Lo for high cholesterol content (40–50%). At these concentrations the cholesterol molecules arrange themselves in linear clusters. Our simulations provide evidence for coexistence between the Lo and gel phases at low temperatures, while at high temperatures the transition from the liquid disordered phase to the Lo phase is continuous and coexistence is not observed. The lipid molecules dynamics depends strongly on temperature and cholesterol concentration. At 323 K and short times, t ∼ 0.1 μs the lipid molecules’ feature an anomalous sub-diffusive behavior with the mean square displacement (MSD) scaling as ∼t1/2. The characteristic time needed to reach the diffusive regime MSD ∼t, increases with the cholesterol content, reaching 0.2 μs for 40% cholesterol content. The lipid diffusion activation energy in the Lo phase is 57 kJ/mol, in good agreement with the available experimental estimates.

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