Computational Elucidation of Co-solvent Effects on Proteins and Hydrophobic Polymers:
Deep eutectic components and biocompatible salts have emerged as powerful agents to counteract the deleterious, denaturing effects of urea on proteins. Using atomistic molecular dynamics simulations, we demonstrate that the folding/unfolding equilibrium of a model protein in an aqueous medium can be finely tuned using a ternary mixture containing choline chloride and urea. While denaturants like urea typically unfold proteins by directly interacting with the peptide backbone—as observed in our binary control simulations where a 15-residue S-peptide analogue is completely distorted—the addition of choline chloride
(at a 1:5 molar ratio) helps the peptide regain most of its native structure. Extending this framework to assess generality, we investigated how choline chloride impacts structurally diverse protein types. Our simulations reveal that in these ternary mixtures, both urea and choline chloride are preferentially excluded from the peptide surface, driving osmolyte-like structural protection. We have analyzed this protective mechanism in meticulous detail, focusing specifically on the local hydrogen-bonding networks and the rotational dynamics
of the choline chloride molecules.
Relevant Publications:
1. Choline Chloride as a Protective Osmolyte: Comparative Stabilization of HP36, Trp-Cage, and GB1 Against Urea Denaturation - Pooja Nanavare and Rajarshi Chakrabarti J. Phys. Chem. B, 129, 11500 (2025).
2. Unveiling the Effect of Choline Chloride on Hydrophobic Association of Methane - Pooja Nanavare and Rajarshi Chakrabarti Phys. Chem. Chem. Phys. 27, 19265 (2025). (This article is part of the themed collection: Structure and dynamics of chemical systems: Honouring N. Sathyamurthy’s 75th birthday).
3. Osmolyte-induced Conformational Stabilization of a Hydrophobic Polymer - Pooja Nanavare, Soham Sarkar, Abhijit Bijay Jena, and Rajarshi Chakrabarti Phys. Chem. Chem. Phys. 26, 24021 (2024).
4. Dynamics of a Methane Hydrophobe in Aqueous Choline Chloride Solution: Insights from Molecular Dynamics Simulations - Pooja Nanavare, Ligesh Theyancheri, Soham Sarkar and Rajarshi Chakrabarti, Chem. Phys. Impact 6, 100223 (2023).
5. Structure and Orientation of Water and Choline Chloride Molecules Around a Methane Hydrophobe: A Computer Simulation Study - Pooja Nanavare, Asha Rani Choudhury, Soham Sarkar, Atanu Maity and Rajarshi Chakrabarti ChemPhysChem 23, e202200446 (2022). (Special Collection Issue: Theoretical Chemistry Symposium 2021). This article has appeared as a Cover Feature of the Journal.
6. In silico Elucidation of Molecular Picture of Water-Choline Chloride Mixture - Soham Sarkar, Atanu Maity and Rajarshi Chakrabarti, J. Phys. Chem. B, 125, 13212 (2021).
7. Microscopic Structural Features of Water in Aqueous-Reline Mixture of varying Compositions - Soham Sarkar, Atanu Maity and Rajarshi Chakrabarti, Phys. Chem. Chem. Phys. 23, 3779 (2021).
8. Choline chloride as a nano-crowder protects HP-36 from urea-induced denaturation: Insights from Solvent Dynamics and Protein-Solvent interaction - Atanu Maity, Soham Sarkar, Ligesh Theeyancheri and Rajarshi Chakrabarti, ChemPhysChem 21, 552 (2020).
9. Ammonium-based stabilizers effectively counteract the Urea-conferred denaturation in a small protein: Insights from molecular dynamics simulations - Soham Sarkar, Soumadwip Ghosh and Rajarshi Chakrabarti, RSC Adv. 7, 52888 (2017).
10. Can ammonium-based room temperature ionic liquid counteract the urea-induced denaturation of a small peptide? - Soumadwip Ghosh, Souvik Dey, Mahendra Patel and Rajarshi Chakrabarti, Phys. Chem. Chem. Phys. 19, 7772 (2017). (This article has been featured in an online themed collection: New Frontiers in Indian Research).