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

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      PLoS Computational Biology

      Public Library of Science

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          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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              This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is (c) 2005 Wiley Periodicals, Inc.

                Author and article information

                Role: Editor
                PLoS Comput Biol
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                November 2008
                November 2008
                14 November 2008
                : 4
                : 11
                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.

                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.
                Pages: 10
                Research Article
                Biophysics/Protein Folding
                Biophysics/Theory and Simulation
                Computational Biology/Molecular Dynamics

                Quantitative & Systems biology


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