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On the stability of chymotrypsin inhibitor 2 in a 10 M urea solution: the role of interaction energies for urea-induced protein denaturation
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
2010 (Engelska)Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 12, nr 32, s. 9358-9366Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Molecular dynamics simulations of chymotrypsin inhibitor 2 in both water and in 10 M urea have been compared with respect to the energies of interaction between protein and solvent. The analysis yield clear and detailed information regarding the enthalpic driving force of urea-induced protein denaturation. The protein is kept in the folded structure by applying positional restraints on the alpha-carbons, thereby creating an equilibrium system from which appropriate driving forces for denaturation can be obtained. All protein atoms are classified as belonging to the backbone, the polar side chains or to the hydrophobic side chains. The interaction energies are extracted for each class separately. The commonly proposed mechanisms of urea denaturation, i.e. that urea interacts mainly with the backbone or with the hydrophobic side chains, can then be tested. The results show that urea decreases the Lennard-Jones interaction energies between protein and solvent by a large amount. The electrostatic energies are almost unaffected by the switch of solvent. The energetically favorable interaction between CI2 and the urea solvent will function as a driving force for the protein to increase its solvent accessible surface area as compared to the folded protein in water. The magnitude of the decrease in the Lennard-Jones energies for the hydrophobic and the hydrophilic side chains and for the backbone were similar. We therefore conclude that urea interacts favorably with the whole protein surface and that all parts of the protein are important in urea-induced denaturation.

Ort, förlag, år, upplaga, sidor
Cambridge: RSC publishing , 2010. Vol. 12, nr 32, s. 9358-9366
Nyckelord [en]
urea, chemical denaturation, protein unfolding, md simulation, molecular dynamics simulation
Nationell ämneskategori
Fysikalisk kemi
Forskningsämne
fysikalisk kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-35289DOI: 10.1039/b925726hISI: 000280708400028PubMedID: 20563326OAI: oai:DiVA.org:umu-35289DiVA, id: diva2:342884
Tillgänglig från: 2010-08-11 Skapad: 2010-08-11 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. On the mechanism of Urea-induced protein denaturation
Öppna denna publikation i ny flik eller fönster >>On the mechanism of Urea-induced protein denaturation
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Department of Chemistry, Umeå university, 2010. s. 52
Nyckelord
Chemical denaturation, Protein unfolding, urea, MD simulations, NMR spectroscopy
Nationell ämneskategori
Fysikalisk kemi
Forskningsämne
fysikalisk kemi
Identifikatorer
urn:nbn:se:umu:diva-33151 (URN)978-91-7264-997-2 (ISBN)
Disputation
2010-05-07, KBC huset, KB3A9, Umeå Universitet, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-04-16 Skapad: 2010-04-13 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Lindgren, MatteusWestlund, Per-Olof

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