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In response to stress in the environment, many organisms respond by accumulating molecularly small solutes termed osmolytes. Curiously, two osmolytes, TMAO and urea, act together in elasmobranchs such as sharks to form solutions at molar concentrations whose net action is close to that of pure water. Although it is known that many osmolytes exert an apparent attractive or repulsive force between self-assembled lipid membranes, all proposed models fail to fully account for the origin of this force. Toward resolving the mechanism by which osmolytes modulate lipid interactions, we followed several osmolytes, including urea and TMAO, and their interaction with lipid membranes in aqueous solution. [1] We found that TMAO pushes adjacent membranes closer together, while urea makes membranes swell. Experiments and simulations further show that the change in the force between membranes is due to the partitioning of TMAO away from the volume between bilayers. This in turn stems from the exclusion of TMAO from the lipid-water interface. Hence, the underlying mechanism resembles protein stabilization by osmolytes. By contrast urea is almost equally partitioned in lipid and bulk, and its action is mostly related to modified van der Waals interactions. Interestingly, urea and TMAO act synergistically, so that the presence of one changes the preferential interaction of the other with lipids. We discuss the potential role of osmolytes acting together in the modifications of lipid adhesion and fusion processes. References [1] S.

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