The osmophobic effect: natural selection of a thermodynamic force in protein folding 1 1Edited by D. Draper

Bolen, D. Wayne; Baskakov, Ilia V.

doi:10.1006/jmbi.2001.4819

Cited by 606 publications

(532 citation statements)

References 28 publications

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“…The exclusion energies of the polar protein stabilizing osmolytes from the hydrophobic HPC chain, however, are comparable to the energies that have been ascribed to exclusion from the peptide backbone (8,11,26). This indicates that the exclusion of these osmolytes from nonpolar peptide side chains should significantly contribute to the stabilization of native protein structure.…”

mentioning

confidence: 70%

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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confidence: 70%

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

Stanley

Rau

2008

Biochemistry

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“…Osmolytes have been previously shown to play important roles in protein folding, packing, and conformation. The proposed mechanism to explain this property of osmolytes is based on the solvophobic effect (36,39), which drives polypeptides to exclude osmolyte molecules from the protein surface by stabilizing a folded conformation that minimizes their solute-exposed surface area. In this regard, it seems that bivalent Fab complexation involves adoption by the mono-Fab of a specific folding/packing conformation that either mediates or accompanies bivalency.…”

Section: Discussionmentioning

confidence: 99%

IgG Fab Fragments Forming Bivalent Complexes by a Conformational Mechanism That Is Reversible by Osmolytes

Nelson

Hoffmann

Parks

et al. 2012

Journal of Biological Chemistry

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Background: Isolated Fab fragments can spontaneously multimerize over time. Results: Distinct conformations are associated with monovalent Fabs versus those in bivalent complexes. Conclusion: Monovalency can be preserved upon conformational stabilization with osmolytes. Significance: A conformational mechanism-informed means for preserving monovalent Fabs increases their potential for use as blocking reagents in clinical applications.

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“…By contrast, many stabilizing solutes do not bind to proteins; indeed, they are excluded from a protein's hydration layer (the water molecules adjacent to a protein's surface) (Timasheff, 1992). Recently termed the 'osmophobic' effect by Bolen and Baskakov (2001), exclusion arises from an apparent repulsion between stabilizers and the peptide backbone, explaining how this effect can be universal. Because of this repulsion, proteins will tend to fold up more compactly, since this will reduce exposure of the peptide-bond backbone to thermodynamically unfavorable interactions with the stabilizing solute (Fig.·5A,B).…”

Section: Mechanisms Of Stabilizationmentioning

confidence: 99%

Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses

Yancey

2005

Journal of Experimental Biology

1,519

1,241

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SUMMARY Organic osmolytes are small solutes used by cells of numerous water-stressed organisms and tissues to maintain cell volume. Similar compounds are accumulated by some organisms in anhydrobiotic, thermal and possibly pressure stresses. These solutes are amino acids and derivatives,polyols and sugars, methylamines, methylsulfonium compounds and urea. Except for urea, they are often called `compatible solutes', a term indicating lack of perturbing effects on cellular macromolecules and implying interchangeability. However, these features may not always exist, for three reasons. First, some of these solutes may have unique protective metabolic roles, such as acting as antioxidants (e.g. polyols, taurine, hypotaurine),providing redox balance (e.g. glycerol) and detoxifying sulfide (hypotaurine in animals at hydrothermal vents and seeps). Second, some of these solutes stabilize macromolecules and counteract perturbants in non-interchangeable ways. Methylamines [e.g. trimethylamine N-oxide (TMAO)] can enhance protein folding and ligand binding and counteract perturbations by urea (e.g. in elasmobranchs and mammalian kidney), inorganic ions, and hydrostatic pressure in deep-sea animals. Trehalose and proline in overwintering insects stabilize membranes at subzero temperatures. Trehalose in insects and yeast,and anionic polyols in microorganisms around hydrothermal vents, can protect proteins from denaturation by high temperatures. Third, stabilizing solutes appear to be used in nature only to counteract perturbants of macromolecules,perhaps because stabilization is detrimental in the absence of perturbation. Some of these solutes have applications in biotechnology, agriculture and medicine, including in vitro rescue of the misfolded protein of cystic fibrosis. However, caution is warranted if high levels cause overstabilization of proteins.

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The osmophobic effect: natural selection of a thermodynamic force in protein folding 1 1Edited by D. Draper

Cited by 606 publications

References 28 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

IgG Fab Fragments Forming Bivalent Complexes by a Conformational Mechanism That Is Reversible by Osmolytes

Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses

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