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Published online before print November 22, 2006
Protein Science, DOI: 10.1110/ps.062393707
 Copyright © 2006 The Protein Society
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The effects of cosolutes on protein dynamics: The reversal of denaturant-induced protein fluctuations by trimethylamine N-oxide

Vicky Doan-Nguyen1 and J. Patrick Loria

Department of Chemistry Yale University, New Haven, Connecticut 06520, USA

(RECEIVED June 8, 2006; FINAL REVISION August 30, 2006; ACCEPTED October 10, 2006)

The protein stabilizing effects of the small molecule osmolyte, trimethylamine N-oxide, against chemical denaturant was investigated by NMR spin-relaxation measurements and model-free analysis. In the presence of 0.7 M guanidine hydrochloride increased picosecond-nanosecond dynamics are observed in the protein ribonuclease A. These increased fluctuations occur throughout the protein, but the most significant increases in flexibility occur at positions believed to be the first to unfold. Addition of 0.35 M trimethylamine N-oxide to this destabilized form of ribonuclease results in significant rigidification of the protein backbone as assessed by 1H-15N order parameters. Statistically, these order parameters are the same as those measured in native ribonuclease indicating that TMAO reduces the amplitude of backbone fluctuations in a destabilized protein. These data suggest that TMAO restricts the bond vector motions on the protein energy landscape to resemble those motions that occur in the native protein and points to a relation between stability and dynamics in this enzyme.

Keywords: guanidine; protein dynamics; protein stability; NMR spin-relaxation; TMAO

1 Present address: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.

Reprint requests to: J. Patrick Loria, Department of Chemistry Yale University, P.O. Box 208107, New Haven, CT 06520, USA; e-mail: Patrick.loria{at}yale.edu; fax: (203) 432-6144.

Supplemental material: see www.proteinscience.org

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.062393707.

Abbreviations: CD, circular dichroism spectroscopy; Gdn, guanidine hydrochloride; MALDI-TOF, matrix assisted laser desorption ionization time of flight; RNase A, bovine pancreatic ribonuclease A; TMAO, trimethylamine N-oxide.


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