A molecular mechanism for osmolyte-induced protein stability

Street, Timothy O.; Bolen, D. Wayne; Rose, George D.

doi:10.1073/pnas.0606236103

Cited by 624 publications

(616 citation statements)

References 38 publications

(38 reference statements)

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“…Several groups have begun examining preferential hydration contributions from the dependence of exclusion on the chemical character of the exposed surface (33)(34)(35). Bolen and coworkers (11,36), for example, have measured the dependence of the solubility of amino acids and amino acid derivatives on solute concentration in order to estimate the contributions from the peptide backbone and side chains. The Schellman model (37) is commonly taken as the physical basis for exclusion, combining steric exclusion or crowding and a relative solute-water binding constant for solvation interactions with the macromolecule.…”

Section: Discussionmentioning

confidence: 99%

Assessing the Interaction of Urea and Protein-Stabilizing Osmolytes with the Nonpolar Surface of Hydroxypropylcellulose

Stanley

Rau

2008

Biochemistry

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The interaction of urea and several naturally occurring protein stabilizing osmolytes, glycerol, sorbitol, glycine betaine, trimethylamine oxide (TMAO), and proline, with condensed arrays of a hydrophobically modified polysaccharide, hydroxypropylcellulose (HPC), has been inferred from the effect of these solutes on the forces acting between HPC polymers. Urea interacts only very weakly. The protein stabilizing osmolytes are strongly excluded. The observed energies indicate that the exclusion of the protein stabilizing osmolytes from protein hydrophobic side chains would add significantly to protein stability. The temperature dependence of exclusion indicates a significant enthalpy contribution to the interaction energy in contrast to expectations from 'molecular crowding' theories based on steric repulsion. The dependence of exclusion on the distance between HPC polymers rather indicates that perturbations of water structuring or hydration forces underlie exclusion.Solutes are widely used to modulate the stability of native or folded conformations of proteins and nucleic acids (1-7). There are several naturally occurring osmolytes that cells synthesize to protect proteins in response to denaturing environmental conditions such as heat shock. Stabilization of compact structures typically results from an increased exclusion of solutes from the unfolded or more open conformations. There is an unfavorable interaction of solutes with exposed surfaces. The exclusion of osmolytes from surfaces necessarily means the inclusion of water and has quite naturally been termed a preferential hydration (6). Excluded, stabilizing osmolytes that are naturally occurring include glycerol, sorbitol, glycine betaine, proline, and trimethylamine oxide (TMAO) (8). Denaturation results when there are favorable interactions of solutes with exposed surface; more solutes are 'bound' or included with unfolded structures. Urea is probably the best known denaturant. The nature of the interaction between the solute and the macromolecule that results in exclusion or inclusion has not been satisfactorily characterized. Crowding theories that have been successful for the interaction of macromolecules (9) have been reformulated for small solute-macromolecule forces (10). This, however, does not explain the chemical specificity of the interaction. Bolen and coworkers, for example, have concluded (8,11,12) that the inclusion of urea and the exclusion of stabilizing osmolytes from proteins are dominated by the interaction of these small molecules with the peptide backbone with little contribution from the exclusion of these polar solutes from hydrophobic side chains. One method for elucidating the physics of the interaction is to measure the distance dependence of the force through either a radial distribution function of solutes †

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Section: Discussionmentioning

confidence: 99%

Assessing the Interaction of Urea and Protein-Stabilizing Osmolytes with the Nonpolar Surface of Hydroxypropylcellulose

Stanley

Rau

2008

Biochemistry

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“…Stabilization can also arise when the free energy of transferring a peptide bond from a dilute aqueous solution to an aqueous solution containing the cosolute is unfavorable (Timasheff 1993). This preferential hydration of N is stabilizing because unfolding exposes more backbone to cosolutes (Street et al 2006). In summary, unlike hardcore repulsions, which are always stabilizing, non-specific interactions can be stabilizing or destabilizing.…”

Section: Introductionmentioning

confidence: 99%

Soft interactions and crowding

2013

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The intracellular milieu is complex, heterogeneous and crowded-an environment vastly different from dilute solutions in which most biophysical studies are performed. The crowded cytoplasm excludes about a third of the volume available to macromolecules in dilute solution. This excluded volume is the sum of two parts: steric repulsions and chemical interactions, also called soft interactions. Until recently, most efforts to understand crowding have focused on steric repulsions. Here, we summarize the results and conclusions from recent studies on macromolecular crowding, emphasizing the contribution of soft interactions to the equilibrium thermodynamics of protein stability. Despite their non-specific and weak nature, the large number of soft interactions present under many crowded conditions can sometimes overcome the stabilizing steric, excluded volume effect.

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“…It has been found that osmolytes such as TMAO can enhance protein folding, ligand binding and can counteract perturbations caused by urea or inorganic ions [22][23][24] . Therefore, it is possible that TMAO affects the structure of receptors and peptide hormones such as Ang II, and may be not only a marker of increased cardiovascular risk, but also a mediator in etiology of cardiovascular diseases.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Trimethylamine-N-Oxide: A Carnitine-Derived Metabolite That Prolongs the Hypertensive Effect of Angiotensin II in Rats

Ufnal

Jaźwiec

Dadlez

et al. 2014

Canadian Journal of Cardiology

185

130

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A molecular mechanism for osmolyte-induced protein stability

Abstract: CorrectionsNEUROSCIENCE. For the article ''A molecular neuroethological approach for identifying and characterizing a cascade of behaviorally regulated genes,''

Cited by 624 publications

References 38 publications

Assessing the Interaction of Urea and Protein-Stabilizing Osmolytes with the Nonpolar Surface of Hydroxypropylcellulose

Assessing the Interaction of Urea and Protein-Stabilizing Osmolytes with the Nonpolar Surface of Hydroxypropylcellulose

Soft interactions and crowding

Trimethylamine-N-Oxide: A Carnitine-Derived Metabolite That Prolongs the Hypertensive Effect of Angiotensin II in Rats

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