Mechanism of urea and TMAO counteraction in lipid membrane interactions.

Abstract

To cope with stress induced by high salinity and hydrostatic pressure, some marine animals accumulate small organic solutes called osmolytes. Most notable among these osmolytes are the denaturant urea, and trimethylamine N-oxide (TMAO) that is known to stabilize proteins. Although TMAO and urea are well known to act together in sharks and other elasmobranchs to form solutions at molar concentrations whose net action on macromolecules is close to that of pure water, the mechanism for this counteraction is still debated. Our study focuses on this effect as seen in the forces acting between lipid bilayers. We found that TMAO pushes adjacent membranes closer together, while urea makes membranes swell. At a specific ratio, the combined effect of the two solutes is the similar to pure water. Our experiments and theory indicate that TMAO dehydration is due to preferential partitioning of the solute away from the lipid and subsequent osmotic pressure that acts to bring membranes closer. By contrast, urea acts to increase the distance between lipid membranes mainly because it reduces the van der Waals attraction between bilayers. This mechanism is distinct from the action of urea on proteins because urea does not preferentially interact with the lipid. The action of the two osmolytes is almost additive. Weak synergy between solutes can be rationalized through small changes in membrane structure and properties. We comment on the potential role of osmolytes acting together in the modification of membrane remodeling processes including adhesion and fusion.