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How a chemical protects fish from the extreme pressures of the deep

Trimethylamine N-oxide fortifies hydrogen bonds in water

by Emily Harwitz, special to C&EN
October 25, 2022

Trimethylamine -oxide (TMAO) in water network
Credit: University of Leeds
Computer modeling shows that trimethylamine N-oxide (TMAO) acts as a structural anchor for water under pressure by strengthening hydrogen bonding throughout the solution (red = O, white = H, gray = C, blue = N).

In the freezing, dark depths of the ocean, organisms face pressures over 1,000 times as great as at the water’s surface. Now, scientists have discovered one clue to how deep-sea organisms survive these high pressures. The chemical trimethylamine N-oxide (TMAO)—found in the tissues of many marine organisms—stabilizes the structure of water (Commun. Chem. 2022, DOI: 10.1038/s42004-022-00726-z).

Eight years ago, scientists observed that the deeper in the ocean a fish lived, the higher the concentration of TMAO in its tissues (Proc. Natl. Acad. Sci. U.S.A. 2014, DOI: 10.1073/pnas.1322003111). TMAO is known to stabilize proteins in marine organisms by counteracting the propensity for high pressure to force water inside proteins and denature them, but how was a mystery.

Intrigued, Lorna Dougan, a physicist at the University of Leeds, and her research team wanted to know how TMAO interacts with the water in organisms’ bodies. Using neutron scattering combined with computer modeling, the team analyzed water’s structure on a molecular level, with and without TMAO and under higher and lower pressures. At lower pressures, water molecules form a tetrahedral network via hydrogen bonding. At higher pressures, like the 4 kilobar used in the study, the hydrogen bonds weaken, and water’s structure becomes destabilized.

But in a TMAO solution, water maintains its structure. TMAO is a highly polarizable molecule with a large dipole moment. With its strongly hydrophilic oxygen and weakly hydrophobic methyl groups, TMAO forms strong hydrogen bonds with nearby water molecules, thus strengthening hydrogen bonding throughout the entire solution, the study authors say.

Water is crucial to biomolecular functioning, helping to stabilize enzymes and proteins and maintain the structure of cells. Because of TMAO’s hydrophobic groups, the chemical may contribute to protein stability by being repelled from, instead of forced into, the hydrophilic surface of biomolecules.

Using their model, the researchers also calculated the concentration of TMAO a marine organism would need at a specific depth to counteract the effects of pressure. This ratio matched that observed experimentally in fish and could be used to predict the depth at which organisms can survive.

Toshiko Ichiye, a chemist at Georgetown University who was not involved with the research, says the study is “interesting and important” because it investigates how the cellular environment is changed by a solute, information that can be applied to diverse fields in which a protein needs to be protected from high pressure, such as in the food industry.

Neal Skipper, a physicist at University College London not involved with the study, thinks the study is technically “really impressive,” he says, for the combination of techniques that enable precise quantitative conclusions about how hydrogen bonding is affected by pressure. This study also suggests that “there are conditions where we haven’t looked for life yet where it might exist” in extreme places—on Earth and other planets.



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