PNNL

Abstract

Cholesterol trafficking, which is an essential function in mammalian cells, is intimately connected to molecular-scale interactions through cholesterol modulation of membrane structure and dynamics and interaction with membrane receptors. Since these effects of cholesterol occur on micro- to millisecond timescales, we sought to improve upon the current coarse-grained model of cholesterol-containing membranes to a model that can simulate membranes at these timescales Cholesterol has been shown to thicken the membrane and increase phospholipid tail order between 0-40% cholesterol, above which these effects plateau or slightly decrease. Here, we showed that the published MARTINI coarse-grained force-field for phospholipid (POPC) and cholesterol fails to capture these effects, and we improved MARTINI’s performance by systematically modifying POPC and cholesterol force-field parameters. We adjusted selected phospholipid coarse-grained bond angle potentials to improve agreement of their distributions with atomistic simulations. We verified that the angle correction maintains or slightly improves the agreement of MARTINI with experimentally measured thermal, elastic, and dynamic properties of POPC membranes. In addition, the angle-corrected model improves prediction of the thickening and ordering effects up to 40% cholesterol but overestimates these effects at higher cholesterol concentration. In accordance with prior work that showed the cholesterol rough face methyl groups are important for limiting cholesterol self-association, we revised the coarse-grained representation of these methyls to better match cholesterol-cholesterol radial distribution functions from atomistic simulations. Finally, by using a finer-grained representation of the branched cholesterol tail than MARTINI, we improved predictions of lipid tail order and bilayer thickness across a wide range of concentrations. These results argue for the importance of systematic optimization for coarse-graining biologically important molecules like cholesterol with complicated molecular structure.