Nuclear magnetic resonance studies of aqueous urea solutions

Finer, E.G.; Franks, F.; Tait, M. J.

doi:10.1021/ja00768a004

Cited by 252 publications

(161 citation statements)

References 3 publications

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“…The ␣-domain runs from residues 1-35 and 85-129, whereas the ␤-domain comprises residues 36 -84. Lysozyme has 4 ␣-helices [helix A (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), helix B (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), helix C (90 -100), and helix D (110 -115)], 2 ␤-strands [strand 1 (43-46) and strand 2 (51-54)], a loop (60 -78) region, and a 310-helix (81-85) (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…Insights into the action of urea come largely from experiments that measure transfer free energies of amino acid side chains and peptide backbone (3,7). Based on these experiments, 2 different mechanisms have been proposed: an ''indirect mechanism'' in which urea is presumed to disrupt the structure of water, thus making hydrophobic groups more readily solvated (8)(9)(10)(11)(12)(13); and a ''direct mechanism'' in which urea interacts either directly with the protein backbone, via hydrogen bonds and other electrostatic interactions, or directly with the amino acids through more favorable van der Waals attractions as compared with water (14,15), or both, thus causing the protein to swell, and then denature. Even within the direct mechanism there is controversy over which of the forces is dominant, electrostatic or van der Waals (7,(16)(17)(18).…”

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confidence: 99%

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Urea denaturation by stronger dispersion interactions with proteins than water implies a 2-stage unfolding

Hua

Zhou

Thirumalai

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

495

621

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The mechanism of denaturation of proteins by urea is explored by using all-atom microseconds molecular dynamics simulations of hen lysozyme generated on BlueGene/L. Accumulation of urea around lysozyme shows that water molecules are expelled from the first hydration shell of the protein. We observe a 2-stage penetration of the protein, with urea penetrating the hydrophobic core before water, forming a ''dry globule.'' The direct dispersion interaction between urea and the protein backbone and side chains is stronger than for water, which gives rise to the intrusion of urea into the protein interior and to urea's preferential binding to all regions of the protein. This is augmented by preferential hydrogen bond formation between the urea carbonyl and the backbone amides that contributes to the breaking of intrabackbone hydrogen bonds. Our study supports the ''direct interaction mechanism'' whereby urea has a stronger dispersion interaction with protein than water.denaturing mechanism ͉ dry globule ͉ molecular dynamics ͉ preferential binding ͉ lysozyme unfolding

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Urea denaturation by stronger dispersion interactions with proteins than water implies a 2-stage unfolding

Hua

Zhou

Thirumalai

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

495

621

View full text Add to dashboard Cite

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“…1. Chaotropic cosolvents are less strongly polar than water, acting in an aqueous solution of hydrophobic particles to reduce the extent of hydrogen bonding between water molecules in both shell and bulk sites [23,51]. Within the adapted MLG framework, this effect is re-produced by the creation of disordered states, with additional broken hydrogen bonds and higher enthalpy, from the more strongly bonded ordered clusters (dashed arrows in Fig.…”

Section: B Cosolvent Additionmentioning

confidence: 99%

Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability

Moelbert

Normand

Rios³

2004

Biophysical Chemistry

190

113

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Kosmotropic cosolvents added to an aqueous solution promote the aggregation of hydrophobic solute particles, while chaotropic cosolvents act to destabilise such aggregates. We discuss the mechanism for these phenomena within an adapted version of the two-state Muller-Lee-Graziano model for water, which provides a complete description of the ternary water/cosolvent/solute system for small solute particles. This model contains the dominant effect of a kosmotropic substance, which is to enhance the formation of water structure. The consequent preferential exclusion both of cosolvent molecules from the solvation shell of hydrophobic particles and of these particles from the solution leads to a stabilisation of aggregates. By contrast, chaotropic substances disrupt the formation of water structure, are themselves preferentially excluded from the solution, and thereby contribute to solvation of hydrophobic particles. We use Monte Carlo simulations to demonstrate at the molecular level the preferential exclusion or binding of cosolvent molecules in the solvation shell of hydrophobic particles, and the consequent enhancement or suppression of aggregate formation. We illustrate the influence of structure-changing cosolvents on effective hydrophobic interactions by modelling qualitatively the kosmotropic effect of sodium chloride and the chaotropic effect of urea.

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“…The physical nature of the direct interactions between proteins and urea is also subject of debate, with some authors suggesting that it is mostly electrostatic and related to the formation of direct hydrogen bonds (5,7,12,13), and others suggest that dispersion interactions are the main factor (14,15). Some authors supported the idea the denaturing role of urea is not related to the formation of direct urea-protein interactions, but to its ability to "dry" the protein, weakening the hydrophobic effect responsible for stabilizing protein structures (16)(17)(18)(19). However, recent consensus is that this indirect mechanism is not the main explanation of the effect of urea (18)(19)(20), pointing instead to the direct mechanism.…”

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confidence: 99%

Toward an atomistic description of the urea-denatured state of proteins

Candotti

Esteban‐Martín

Salvatella

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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We present here the characterization of the structural, dynamics, and energetics of properties of the urea-denatured state of ubiquitin, a small prototypical soluble protein. By combining state-of-the-art molecular dynamics simulations with NMR and small-angle X-ray scattering data, we were able to: (i) define the unfolded state ensemble, (ii) understand the energetics stabilizing unfolded structures in urea, (iii) describe the dedifferential nature of the interactions of the fully unfolded proteins with urea and water, and (iv) characterize the early stages of protein refolding when chemically denatured proteins are transferred to native conditions. The results presented herein are unique in providing a complete picture of the chemically unfolded state of proteins and contribute to deciphering the mechanisms that stabilize the native state of proteins, as well as those that maintain them unfolded in the presence of urea.denaturing mechanism | protein unfolding | random coil | ensemble simulation

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Nuclear magnetic resonance studies of aqueous urea solutions

Cited by 252 publications

References 3 publications

Urea denaturation by stronger dispersion interactions with proteins than water implies a 2-stage unfolding

Urea denaturation by stronger dispersion interactions with proteins than water implies a 2-stage unfolding

Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability

Toward an atomistic description of the urea-denatured state of proteins

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