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Polar or Apolar—The Role of Polarity for Urea-Induced Protein Denaturation

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PLoS Computational Biology

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      Abstract

      Urea-induced protein denaturation is widely used to study protein folding and stability; however, the molecular mechanism and driving forces of this process are not yet fully understood. In particular, it is unclear whether either hydrophobic or polar interactions between urea molecules and residues at the protein surface drive denaturation. To address this question, here, many molecular dynamics simulations totalling ca. 7 µs of the CI2 protein in aqueous solution served to perform a computational thought experiment, in which we varied the polarity of urea. For apolar driving forces, hypopolar urea should show increased denaturation power; for polar driving forces, hyperpolar urea should be the stronger denaturant. Indeed, protein unfolding was observed in all simulations with decreased urea polarity. Hyperpolar urea, in contrast, turned out to stabilize the native state. Moreover, the differential interaction preferences between urea and the 20 amino acids turned out to be enhanced for hypopolar urea and suppressed (or even inverted) for hyperpolar urea. These results strongly suggest that apolar urea–protein interactions, and not polar interactions, are the dominant driving force for denaturation. Further, the observed interactions provide a detailed picture of the underlying molecular driving forces. Our simulations finally allowed characterization of CI2 unfolding pathways. Unfolding proceeds sequentially with alternating loss of secondary or tertiary structure. After the transition state, unfolding pathways show large structural heterogeneity.

      Author Summary

      To perform their physiological function, proteins have to fold into their characteristic three-dimensional structure. While the folded state is stable under physiological conditions, changes in the solvent can destabilize the folded state and even induce denaturation. One of the most commonly used denaturants is urea. Despite its widespread use to study protein folding and stability, however, the molecular mechanism and particularly the driving forces of urea-induced protein denaturation are not yet understood. Two mechanisms have been suggested, according to which denaturation is driven either by polar interactions via hydrogen bonds or by hydrophobic interactions with apolar amino acids. By systematically varying urea polarity and quantifying the interactions of the solvent molecules with all amino acids of the protein, the present simulation study reveals that it is mainly the apolar interactions that drive denaturation. Our results suggest a coherent microscopic picture for urea-induced denaturation and bear more general implications for protein stability in other environments, e.g., in chaperone-assisted folding.

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            Author and article information

            Affiliations
            Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany
            Stanford University, United States of America
            Author notes

            Conceived and designed the experiments: MCS HG. Performed the experiments: MCS. Analyzed the data: MCS. Wrote the paper: MCS HG.

            Contributors
            Role: Editor
            Journal
            PLoS Comput Biol
            plos
            ploscomp
            PLoS Computational Biology
            Public Library of Science (San Francisco, USA)
            1553-734X
            1553-7358
            November 2008
            November 2008
            14 November 2008
            : 4
            : 11
            2570617
            19008937
            08-PLCB-RA-0563R3
            10.1371/journal.pcbi.1000221
            (Editor)
            Stumpe, Grubmüller. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 10
            Categories
            Research Article
            Biophysics/Protein Folding
            Biophysics/Theory and Simulation
            Computational Biology/Molecular Dynamics

            Quantitative & Systems biology

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