Hysteresis and the Cholesterol-Dependent Melting Transition of the Martini Model

Extensive Martini simulation data, totaling 5 ms, is presented for binary mixtures of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol. Using simulations initiated from both gel and liquid-disordered (L d ) phases, significant and strongly cholesterol-dependent hysteresis in the enthalpy as a function of temperature is observed for cholesterol mole fractions from 0 to 20 mol% — adding just a single cholesterol to each leaflet of a pure DPPC bilayer more than doubles the width of the hysteresis loop relative to a pure DPPC bilayer. Although the precise phase transition temperature cannot be determined due to the hysteresis, the data are consistent with a first order gel to fluid transition, which increases in temperature with cholesterol. At 30 mol% cholesterol, no hysteresis is observed, and there is no evidence for a continuous transition, in either structural parameters like the area per lipid or in the heat capacity as a function of temperature. The results are consistent with a single uniform phase above a critical cholesterol composition between 20 and 30 mol% in Martini, while highlighting the importance and difficulty of obtaining the equilibrium averages to locate phase boundaries precisely in computational models of lipid bilayers.