Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: A chemical chaperone at atomic resolution

Brian J. Bennion, Valerie Daggett

Research output: Contribution to journalArticle

235 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6433-6438
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number17
DOIs
StatePublished - Apr 27 2004
Externally publishedYes

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Protein Denaturation
Urea
Protein Unfolding
Proteins
trimethyloxamine
Molecular Dynamics Simulation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Counteraction of urea-induced protein denaturation by trimethylamine N-oxide : A chemical chaperone at atomic resolution. / Bennion, Brian J.; Daggett, Valerie.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 17, 27.04.2004, p. 6433-6438.

Research output: Contribution to journalArticle

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