Unlocking the full compositional control of hydrophilic and hydrophobic deep eutectic solvents over protein structure and stability

Adrian Sanchez-Fernandez; Jake H. Nicholson; Susana M. Meza Huaman; Claudia Almuzara Romero; Jia Fei Poon; Sylvain Prevost; Alex P.S. Brogan

doi:10.1038/s42004-025-01571-6

Unlocking the full compositional control of hydrophilic and hydrophobic deep eutectic solvents over protein structure and stability

Adrian Sanchez-Fernandez^*, Jake H. Nicholson, Susana M. Meza Huaman, Claudia Almuzara Romero, Jia Fei Poon, Sylvain Prevost, Alex P.S. Brogan^*

^*Corresponding author for this work

Chemistry

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Abstract

Deep eutectic solvents (DESs) have emerged as powerful environments to enhance enzymatic reactions, formulate therapeutic proteins, and develop protein-based biomaterials. Despite the wide range of properties that could be achievable through the compositional design of DESs, protein solubilization only happens in a relatively narrow range of hydrophilic DESs. Here, we use surface-modification for the generalized solubilization of proteins in both hydrophilic and hydrophobic DESs. Using surface-modified myoglobin as a model, we show that both DES polarity and hydrogen bond capacity play important roles in dictating the conformational state of the protein. In the hydrophilic DES the protein displays a near-native conformation with an improvement of the thermal stability of + 28 °C compared to aqueous solutions. In contrast, hydrophobic DESs stabilize partially folded intermediates which can refold from temperatures as high as 190 °C. As such, our approach provides a platform to generalize protein incorporation into anhydrous DESs that could be exploited in biocatalysis, biomolecule stabilization, and biomaterials. (Figure presented.)

Original language	English
Article number	173
Journal	Communications Chemistry
Volume	8
Issue number	1
Early online date	5 Jun 2025
DOIs	https://doi.org/10.1038/s42004-025-01571-6
Publication status	E-pub ahead of print - 5 Jun 2025

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Sanchez-Fernandez, A., Nicholson, J. H., Meza Huaman, S. M., Almuzara Romero, C., Poon, J. F., Prevost, S., & Brogan, A. P. S. (2025). Unlocking the full compositional control of hydrophilic and hydrophobic deep eutectic solvents over protein structure and stability. Communications Chemistry, 8(1), Article 173. Advance online publication. https://doi.org/10.1038/s42004-025-01571-6

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abstract = "Deep eutectic solvents (DESs) have emerged as powerful environments to enhance enzymatic reactions, formulate therapeutic proteins, and develop protein-based biomaterials. Despite the wide range of properties that could be achievable through the compositional design of DESs, protein solubilization only happens in a relatively narrow range of hydrophilic DESs. Here, we use surface-modification for the generalized solubilization of proteins in both hydrophilic and hydrophobic DESs. Using surface-modified myoglobin as a model, we show that both DES polarity and hydrogen bond capacity play important roles in dictating the conformational state of the protein. In the hydrophilic DES the protein displays a near-native conformation with an improvement of the thermal stability of + 28 °C compared to aqueous solutions. In contrast, hydrophobic DESs stabilize partially folded intermediates which can refold from temperatures as high as 190 °C. As such, our approach provides a platform to generalize protein incorporation into anhydrous DESs that could be exploited in biocatalysis, biomolecule stabilization, and biomaterials. (Figure presented.)",

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AU - Sanchez-Fernandez, Adrian

AU - Nicholson, Jake H.

AU - Meza Huaman, Susana M.

AU - Almuzara Romero, Claudia

AU - Poon, Jia Fei

AU - Prevost, Sylvain

AU - Brogan, Alex P.S.

PY - 2025/6/5

Y1 - 2025/6/5

N2 - Deep eutectic solvents (DESs) have emerged as powerful environments to enhance enzymatic reactions, formulate therapeutic proteins, and develop protein-based biomaterials. Despite the wide range of properties that could be achievable through the compositional design of DESs, protein solubilization only happens in a relatively narrow range of hydrophilic DESs. Here, we use surface-modification for the generalized solubilization of proteins in both hydrophilic and hydrophobic DESs. Using surface-modified myoglobin as a model, we show that both DES polarity and hydrogen bond capacity play important roles in dictating the conformational state of the protein. In the hydrophilic DES the protein displays a near-native conformation with an improvement of the thermal stability of + 28 °C compared to aqueous solutions. In contrast, hydrophobic DESs stabilize partially folded intermediates which can refold from temperatures as high as 190 °C. As such, our approach provides a platform to generalize protein incorporation into anhydrous DESs that could be exploited in biocatalysis, biomolecule stabilization, and biomaterials. (Figure presented.)

AB - Deep eutectic solvents (DESs) have emerged as powerful environments to enhance enzymatic reactions, formulate therapeutic proteins, and develop protein-based biomaterials. Despite the wide range of properties that could be achievable through the compositional design of DESs, protein solubilization only happens in a relatively narrow range of hydrophilic DESs. Here, we use surface-modification for the generalized solubilization of proteins in both hydrophilic and hydrophobic DESs. Using surface-modified myoglobin as a model, we show that both DES polarity and hydrogen bond capacity play important roles in dictating the conformational state of the protein. In the hydrophilic DES the protein displays a near-native conformation with an improvement of the thermal stability of + 28 °C compared to aqueous solutions. In contrast, hydrophobic DESs stabilize partially folded intermediates which can refold from temperatures as high as 190 °C. As such, our approach provides a platform to generalize protein incorporation into anhydrous DESs that could be exploited in biocatalysis, biomolecule stabilization, and biomaterials. (Figure presented.)

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Unlocking the full compositional control of hydrophilic and hydrophobic deep eutectic solvents over protein structure and stability

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