TMAO mediates effective attraction between lipid membranes by partitioning unevenly between bulk and lipid domains

Abstract

Under environmental duress, many organisms accumulate large amounts of osmolytes - molecularly small organic solutes. Osmolytes are known to counteract stress, driving proteins to their compact native states by their exclusion from protein surfaces. In contrast, the effect of osmolytes on lipid membranes is poorly understood and widely debated. Many fully membrane-permeable osmolytes exert an apparent attractive force between lipid membranes, yet all proposed models fail to fully account for the origin of this force. We follow the quintessential osmolyte trimethylamine N-oxide (TMAO) and its interaction with dimyristoyl phosphatidylcholine (DMPC) membranes in aqueous solution. We find that by partitioning away from the inter-bilayer space, TMAO pushes adjacent membranes closer together. Experiments and simulations further show that the partitioning of TMAO away from the volume between bilayers stems from its exclusion from the lipid-water interface, similar to the mechanism of protein stabilization by osmolytes. We extend our analysis to show that the preferential interaction of other physiologically relevant solutes (including sugars and DMSO) also correlates with their effect on membrane bilayer interactions. Our study resolves a long-standing puzzle, explaining how osmolytes can increase membrane-membrane attraction or repulsion depending on their preferential interactions with lipids.

Influence of polar co-solutes and salt on the hydration of lipid membranes

“…In an earlier study by Sukenik et al, 24 TMAO was reported to dehydrate bilayer systems under excess water conditions when TMAO is in a phase-separated aqueous phase. Here we show that the trend is reversed in the absence of excess water, which is the relevant boundary condition in the stratum corneum.…”

“…It was previously shown that the partitioning of co-solutes within multilamellar membrane systems is sensitive to the co-solutes' preferential interactions with the membrane surfaces. 23,24 It is therefore likely that co-solute/membrane preferential interactions are of relevance also for the membranes' short-range repulsion. 53 Fig.…”

“…[20][21][22] More recently, it was shown that TMAO, in contrast to urea, exhibits unfavorable interactions with lipid headgroups and is therefore preferentially expelled from membrane multilayers via precipitation at very dry conditions 23 or by partitioning into the excess aqueous medium when present. 24 In a wide range of dehydrating osmotic pressures, however, both urea and TMAO remain confined between the membrane surfaces. 23 In the present work, we investigate the influence of cosolutes on the hydration repulsion between lipid membranes, the interfacial force that ultimately governs the hydration level of membrane systems subject to osmotic stress.…”

The plant dehydrin Lti30 stabilizes lipid lamellar structures in varying hydration conditions

“…Far simpler approaches found in nature involve the use of small polar (osmolyte) molecules, such as sugars, free amino acids, urea, glycerol, and TMAO (13,14,16,18,50,(54)(55)(56)(57). The mechanism by which these small molecules protect the biological systems against osmotic stress is different from that of the dehydrins and may also be different between the different osmolyte compounds (29,32,58). The last question addressed in this article concerns the similarities and differences between dehydrin Lti30 and small polar osmolytes in their effects on lipid membrane systems at varying hydration conditions.…”

“…The osmolytes used for these studies, urea and TMAO, are typically not found in plants but serve as model compounds to illustrate general molecular mechanisms. Urea and TMAO were chosen as model osmolytes because their effects on lipid membranes in dry conditions have previously been well characterized (29)(30)(31)(32).…”