BIOPHYSICAL THEORY AND MODELING |
Osmolyte trimethylamine-N-oxide (TMAO) does not affect
the strength of hydrophobic interactions: Origin of
osmolyte compatibility
Manoj V. Athawale 1, Jonathan S. Dordick 1 and Shekhar Garde 1*
1 Rensselaer Polytechnic Institute
* To whom correspondence should be addressed. E-mail: gardes{at}rpi.edu.
Submitted on November 19, 2004
Revised on January 4, 2005
Accepted on 6 May 2005
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Abstract |
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Osmolytes are small organic solutes accumulated at high concentrations by cells/tissues in response to osmotic stress. Osmolytes increase thermodynamic stability of folded proteins and provide protection against denaturing stresses. The mechanism of osmolyte compatibility and osmolyte-induced stability has, therefore, attracted considerable attention in recent years. However, to our knowledge, no quantitative study of osmolyte effects on the strength of hydrophobic interactions has been reported. Here, we present a detailed molecular dynamics simulation study of the effect of the osmolyte trimethylamine-N-oxide (TMAO) on hydrophobic phenomena at molecular and nanoscopic lengthscales. Specifically, we investigate effects of TMAO on the thermodynamics of hydrophobic hydration and interactions of small solutes as well as on the folding-unfolding conformational equilibrium of a hydrophobic polymer in water. The major conclusion of our study is that TMAO has almost no effect either on the thermodynamics of hydration of small nonpolar solutes or on the hydrophobic interactions at the pair and manybody level. We propose that this neutrality of TMAO towards hydrophobic interactions -- one of the primary driving forces in protein folding -- is at least partially responsible for making TMAO a "compatible" osmolyte. That is, TMAO can be tolerated at high concentrations in organisms without affecting non-specific hydrophobic effects. Our study implies that protein stabilization by TMAO occurs through other mechanisms, such as unfavorable water-mediated interaction of TMAO with the protein backbone, as suggested by recent experimental studies (Baskakov and Bolen, 1998; Bolen and llia V. Baskasov, 2001; Liu and Bolen, 1995; Wang and Bolen, 1997). We complement the above calculations with analysis of TMAO hydration and changes in water structure in the presence of TMAO molecules. TMAO is an amphiphilic molecule containing both hydrophobic and hydrophilic parts. The precise balance of the effects of hydrophobic and hydrophilic segments of the molecule appears to explain the virtual non-effect of TMAO on the strength of hydrophobic interactions.
Key Words:
hydrophobic interactions, manybody effects, osmolyte compatibility, osmolyte effects, self-assembly
