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J. Biol. Chem., Vol. 280, Issue 12, 11035-11042, March 25, 2005

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Counteracting Osmolyte Trimethylamine N-Oxide Destabilizes Proteins at pH below Its pK_a

MEASUREMENTS OF THERMODYNAMIC PARAMETERS OF PROTEINS IN THE PRESENCE AND ABSENCE OF TRIMETHYLAMINE N-OXIDE^*

Rajendrakumar Singh, Inamul Haque, and Faizan Ahmad

From the Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110 025, India

Earlier studies have reported that trimethylamine N-oxide (TMAO), a naturally occurring osmolyte, is a universal stabilizer of proteins because it folds unstructured proteins and counteracts the deleterious effects of urea and salts on the structure and function of proteins. This conclusion has been reached from the studies of the effect of TMAO on proteins in the pH range 6.0–8.0. In this pH range TMAO is almost neutral (zwitterionic form), for it has a pK_a of 4.66 ± 0.10. We have asked the question of whether the effect of TMAO on protein stability is pH-dependent. To answer this question we have carried out thermal denaturation studies of lysozyme, ribonuclease-A, and apo--lactalbumin in the presence of various TMAO concentrations at different pH values above and below the pK_a of TMAO. The main conclusion of this study is that near room temperature TMAO destabilizes proteins at pH values below its pK_a, whereas it stabilizes proteins at pH values above its pK_a. This conclusion was reached by determining the T_m (midpoint of denaturation), H_m (denaturational enthalpy change at T_m), C_p (constant pressure heat capacity change), and G_D° (denaturational Gibbs energy change at 25 °C) of proteins in the presence of different TMAO concentrations. Other conclusions of this study are that T_m and G_D° depend on TMAO concentration at each pH value and that H_m and the C_p are not significantly changed in presence of TMAO.

Received for publication, September 17, 2004 , and in revised form, January 7, 2005.

^* This work was supported by the Council of Scientific and Industrial Research, India and the Department of Science and Technology, India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 91-11-2698-1733; Fax: 91-11-2698-0164; E-mail: faizan_ahmad{at}yahoo.com.

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