Molecular dynamics study of lipid bilayers modeling outer and inner leaflets of plasma membranes of mouse hepatocytes. I. Differences in physicochemical properties between the two leaflets.

Outer and inner leaflets of plasma cell membranes have different lipid compositions, and the membrane properties of each leaflet can differ from each other significantly due to these composition differences. However, because of the experimental difficulty in measuring the membrane properties for each leaflet separately, the differences are not well understood at a molecular level. In this study, we constructed two lipid bilayer systems, modeling outer and inner leaflets of plasma membranes of mouse hepatocytes based on experimental composition data. The ion concentration in the interlamellar water phase was also set to match the concentration in extra- and intracellular fluids. The differences in physical properties between the outer and inner leaflets of mouse hepatocyte cell membrane models were investigated by performing 1.2 μs-long all-atomistic molecular dynamics calculations under physiological temperature and pressure conditions (310.15 K and 1 atm). The calculated electron density profiles along the bilayer normal for each model bilayer system captured well the asymmetric feature of the experimental electron density profile across actual cell plasma membranes, indicating that our procedure of modeling the outer and inner leaflets of the cell plasma membranes was satisfactory. We found that compared to the outer leaflet model, the inner leaflet model had a very bulky and soft structure in the lateral direction. To confirm the differences, membrane fluidity was measured from the lateral diffusivity and relaxation times. The fluidity was significantly higher in the inner leaflet model than in the outer leaflet model. We also discuss two topics that are of wide interest in biology, i.e., the interdigitation of acyl tails of lipid molecules between two monolayers and the lateral concentration fluctuation of lipid molecules in the bilayers.