Can Urea and Trimethylamine-N-oxide Prevent the Pressure-Induced Phase Transition of Lipid Membrane?

Organisms dwelling in ocean trenches are exposed to the high hydrostatic pressure of ocean water. Increasing pressure can alter the membrane packing density and fluidity and trigger the fluid-to-gel phase transition. To combat environmental stress, the organisms synthesize small polar solutes, which are known as osmolytes. Urea and trimethylamine-N-oxide (TMAO) are two such solutes found in deep-sea creatures. While TMAO stabilizes protein, urea induces protein denaturation. These solutes strongly influence the packing density and membrane fluidity of the lipid bilayer at different conditions. But can these solutes affect the pressure-induced phase transition of the lipid membrane? In the present work, we have studied the effect of these two solutes on pressure-induced fluid-to-gel phase transition based on the all-atom molecular dynamics (MD) simulation approach. A high-pressure-stimulated fluid-to-gel phase transition of the membrane is seen at 800 bar, which is consistent with previous experiments. We have also observed that in the low-pressure region (1-400 bar), urea slightly increases the membrane fluidity where TMAO decreases the same. However, the phase transition pressure remains almost unchanged on the addition of urea while TMAO shifts the phase transition toward a lower pressure. We have found that the hydrogen (H)-bond interaction between lipid and urea plays an important role in preserving the fluidity of the membrane in the low-pressure zone. However, at a higher pressure, both water and urea are excluded from the membrane surface. TMAO is also excluded from the interfacial region of the membrane at all pressures. Exclusion from the membrane surface further triggers the phase transition of the lipid membrane from the fluid to gel phase at a high pressure.