ASM 2019

Poster (P41)


Cosolvents Effect on Protein (Un)Folding Equilibrium.

 

Rohit Modee, Aditya Chattopadhyay, Tanashree Jaganade, Shampa Raghunathan and U. Deva Priyakumar

 

Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad 500 032, India

 

Abstract

 

Addition of cosolvents such as urea and trimethylamine N-oxide (TMAO) affects the protein folding equilibrium by shifting it towards the unfolded or folded states. Urea favors unfolded ensemble of proteins, and is therefore known as a denaturant whereas a cosolvent like TMAO which favors folded state is called protectant. Previous computational studies have focused on elucidating the pathway of unfolding and deciphering the molecular mechanism underlying protein N/U equilibrium in presence of urea. Despite of all the available studies on osmolyte mediated protein unfolding, N/U equilibrium in presence of protectant and denaturant is not well understood. To gain insights into the molecular level details of urea interactions with proteins in their unfolded states, we have performed atomistic molecular dynamics simulations on model systems representing side chains of all amino acids in different solvent environments (water and varying concentrations of aqueous urea). Extensive analysis of structural, energetic and dynamic parameters have been done to understand the mechanism at atomic level. Interestingly, almost all amino acids showed preference for urea solvation with the aromatic groups exhibiting the highest preferences followed by hydrophobic groups, followed by amides and basic groups, and the least by nucleophilic groups. To further understand the reversible N/U equilibrium of Trpzip1 monomeric B-hairpin protein in presence of urea and in combination of urea & TMAO, we have performed all-atom replica exchange MD (REMD) simulations. Results show that hydrogen bonds play an important role in forming a B-hairpin structure, along with van der Waals interactions. We identify and quantify these native interactions to use it as a reaction coordinate for reversible N/U equilibrium of trpzip1.

 

References

  1. Goyal, S., Chattopadhyay, A., Kasavajhala, K. & Priyakumar, U. D. Role of Urea-Aromatic Stacking Interactions in Stabilizing the Aromatic Residues of the Protein in Urea-Induced Denatured State. J. Am. Chem. Soc 139, 14931-14946 (2017).
  2. Canchi, D. R., Paschek, D. & Garcia, A. E. Equilibrium study of protein denaturation by urea. J. Am. Chem. Soc. 132, 2338-2344 (2010).
  3. Canchi DR, Garcia AE. Cosolvent effects on protein stability. Annu Rev Phys Chem 64, 273-293 (2013).

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