Relationship between water permeation and flip-flop motion in a bilayer membrane

The lipid bilayer membrane facilitates various biological reactions and is thus an essential structure that sustains all higher forms of life. The unique local environment of the lipid bilayer plays critical roles for the diffusion of biomolecules as well as water molecules in biological reactions. Although fluctuation of the cell membrane is expected to allow for the transport of some water molecules, the flip-flop of lipid molecules corresponds to lipid transport between membrane leaflets, and is considered to be an important process to regulate the lipid composition of biological membranes. However, the relationship between these flip-flop phenomena and surrounding water molecules remains poorly understood. We hypothesized that the flip-flop is caused by water molecules permeating through the cell membrane. To test this hypothesis, we used millisecond-order coarse-grained molecular simulations (dissipative particle dynamics) to investigate the distance between water molecules and lipid molecules depending on the position of the lipid molecule. The results clearly showed that water molecules affect the flip-flop motion in the early stage, but have minimal contribution to the subsequent behavior. Moreover, based on the results of dissipative particle dynamics simulation, we computed several first-passage-time (FPT) quantities to describe the detailed dynamics of water permeation. We modeled arrangements in the middle of the flip-flop process, which were compared with the arrangement without lipid molecules. Overall, our results indicate that lipid molecules located both in perpendicular and parallel arrangements largely affect water permeation. These findings provide new insight into the detailed relationship between water permeation and the flip-flop motion.