Flip-Flop Motions of Lipid Molecules in Mixed Bilayer Systems

Abstract

The cell membrane is composed of a wide variety of lipid molecules, cholesterols, and membrane proteins. Lipid molecules in the membrane have several time scales of motions ranging from femtosecond to seconds. The flip-flop motion, in which lipid molecules move from one leaflet to the other, is known to be one of the slowest: it typically occurs within several tens of seconds, or much longer. Recently, experimental studies revealed that cholesterols (CHOL), diacylglycerols (DAG), and ceramides (CER) show fast flip-flop motions in some membranes. However, the molecular mechanisms underling the motions remain elusive. In this work, we performed coarse-grained molecular dynamics simulations, using MALTINI force field parameters. We examined flip-flop motions of CHOL, DAG, and CER in phospholipid bilayer systems, composing of DAPC(di-20:4), SAPC(18:0-20:4), and POPC(16:0-18:1). In the simulations using DAPC membranes, we observed flip-flop motions of CHOL, DAG, and CER within a microsecond. The flip-flop rate of CHOL was the highest, whereas that of DAG was lower than CHOL. CER flipped only once during the simulation. This tendency of flip-flop motions is strongly correlated with the relative positions of the lipids to the bilayer membranes: CHOL stays almost at the center of the membrane, whereas the head group of CER is located at the water/membrane interface and interacted with solvent molecules strongly. The flip-flop motions of lipids were also affected with the membrane environment. Within 1-microsecond simulations, CHOL flipped 257 times in DAPC, 196 times in SAPC, and 5 times in POPC. Thus, the flip-flop rate is strongly correlated with the number of double bonds in the acyl chains of bilayer phospholipids, suggesting the importance of the membrane fluidity. These simulation results qualitatively agree with existing experimental data and shed light on the molecular mechanisms underlying the dynamics of biomembranes.