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The affect of urea on the kinetics of local unfolding processes in chymotrypsin inhibitor 2
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2010 (English)In: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 151, no 1-2, 46-53 p.Article in journal (Refereed) Published
Abstract [en]

The dynamics of chymotrypsin inhibitor 2 (CI2) in water, as well as in 10M urea, have been studied by Molecular Dynamics simulations. The analysis aims at investigating how local protein processes are affected by urea and how the perturbation by urea on the local level manifests itself in the kinetics of the global unfolding. The results show that the effect of urea on local processes depends upon the type of process at hand. An isolated two-residue contact on the surface of CI2 has a decreased frequency of rupture in the urea solvent. This is in contrast to the increased frequency of rupture of the hydrogen bonds in secondary structure elements in the urea solvent. It is proposed that the increase in the unfolding rates of complex protein processes is based upon the retardation of the refolding rate of small scale, isolated processes.

Place, publisher, year, edition, pages
2010. Vol. 151, no 1-2, 46-53 p.
Keyword [en]
urea, denaturation, chymotrypsin inhibitor 2, kinetics, molecular dynamics, MD simulation
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-35290DOI: 10.1016/j.bpc.2010.05.004ISI: 000280510000007PubMedID: 20570033OAI: oai:DiVA.org:umu-35290DiVA: diva2:342887
Available from: 2010-08-11 Created: 2010-08-11 Last updated: 2017-12-12Bibliographically approved
In thesis
1. On the mechanism of Urea-induced protein denaturation
Open this publication in new window or tab >>On the mechanism of Urea-induced protein denaturation
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It is well known that folded proteins in water are destabilized by the addition of urea. When a protein loses its ability to perform its biological activity due to a change in its structure, it is said to denaturate. The mechanism by which urea denatures proteins has been thoroughly studied in the past but no proposed mechanism has yet been widely accepted. The topic of this thesis is the study of the mechanism of urea-induced protein denaturation, by means of Molecular Dynamics (MD) computer simulations and Nuclear Magnetic Resonance (NMR) spectroscopy.

Paper I takes a thermodynamic approach to the analysis of protein – urea solution MD simulations. It is shown that the protein – solvent interaction energies decrease significantly upon the addition of urea. This is the result of a decrease in the Lennard-Jones energies, which is the MD simulation equivalent to van der Waals interactions. This effect will favor the unfolded protein state due to its higher number of protein - solvent contacts. In Paper II, we show that a combination of NMR spin relaxation experiments and MD simulations can successfully be used to study urea in the protein solvation shell. The urea molecule was found to be dynamic, which indicates that no specific binding sites exist. In contrast to the thermodynamic approach in Paper I, in Paper III we utilize MD simulations to analyze the affect of urea on the kinetics of local processes in proteins. Urea is found to passively unfold proteins by decreasing the refolding rate of local parts of the protein that have unfolded by thermal fluctuations.

Based upon the results of Paper I – III and previous studies in the field, I propose a mechanism in which urea denatures proteins mainly by an enthalpic driving force due to attractive van der Waals interactions. Urea interacts favorably with all the different parts of the protein. The greater solvent accessibility of the unfolded protein is ultimately the factor that causes unfolded protein structures to be favored in concentrated urea solutions.

Place, publisher, year, edition, pages
Umeå: Department of Chemistry, Umeå university, 2010. 52 p.
Keyword
Chemical denaturation, Protein unfolding, urea, MD simulations, NMR spectroscopy
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-33151 (URN)978-91-7264-997-2 (ISBN)
Public defence
2010-05-07, KBC huset, KB3A9, Umeå Universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2010-04-16 Created: 2010-04-13 Last updated: 2010-09-24Bibliographically approved

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Lindgren, MatteusWestlund, Per-Olof

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