Counteraction of Urea-Induced Protein Denaturation by Trimethylamine N-Oxide: A Chemical Chaperone at Atomic Resolution

Proteins are very sensitive to their solvent environments. Urea is a common chemical denaturant of proteins, yet some animals contain high concentrations of urea. These animals have evolved an interesting mechanism to counteract the effects of urea by using trimethylamine N-oxide (TMAO). The molecul...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 17; pp. 6433 - 6438
Main Authors Bennion, Brian J., Daggett, Valerie, Fersht, Alan
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 27.04.2004
National Acad Sciences
Subjects
Atoms & subatomic particles
Biochemistry
Biological Sciences
Biophysics
Chemicals
Crystal structure
Hydrogen bonds
Methylamines - chemistry
Models, Molecular
Molecular dynamics
Molecular mechanisms of action
Molecular structure
Molecules
Protein Denaturation
Proteins
Solvents
Solvents - chemistry
Urea - chemistry
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Summary:Proteins are very sensitive to their solvent environments. Urea is a common chemical denaturant of proteins, yet some animals contain high concentrations of urea. These animals have evolved an interesting mechanism to counteract the effects of urea by using trimethylamine N-oxide (TMAO). The molecular basis for the ability of TMAO to act as a chemical chaperone remains unknown. Here, we describe molecular dynamics simulations of a small globular protein, chymotrypsin inhibitor 2, in 8 M urea and 4 M TMAO/8 M urea solutions, in addition to other control simulations, to investigate this effect at the atomic level. In 8 M urea, the protein unfolds, and urea acts in both a direct and indirect manner to achieve this effect. In contrast, introduction of 4 M TMAO counteracts the effect of urea and the protein remains well structured. TMAO makes few direct interactions with the protein. Instead, it prevents unfolding of the protein by structuring the solvent. In particular, TMAO orders the solvent and discourages it from competing with intraprotein H bonds and breaking up the hydrophobic core of the protein.
Bibliography:This paper was submitted directly (Track II) to the PNAS office.
To whom correspondence should be addressed. E-mail: daggett@u.washington.edu.
Edited by Alan Fersht, University of Cambridge, Cambridge, United Kingdom
Abbreviations: CI2, chymotrypsin inhibitor 2; MD, molecular dynamics; RMSD, RMS deviation; SASA, solvent-accessible surface area; TMAO, trimethylamine N-oxide.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0308633101