The Influence of Urea and Trimethylamine-<i>N</i>-oxide on Hydrophobic Interactions

Paul, Sandip; Patey, G. N.

doi:10.1021/jp0733668

Cited by 63 publications

(70 citation statements)

References 12 publications

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“…Therefore, as expected, the unfolding forces estimated from the PMF (see Fig. 2B and Table 1) for both PS 20 and PS 40 are significantly smaller than those measured experimentally for much longer chains. This force increases as the polymer gets longer because there are more interacting sites; direct quantitative comparison with experiment requires extrapolation of the simulation data to much longer chain lengths.…”

Section: Resultssupporting

confidence: 77%

“…The only experimental study on hydrophobic clustering in the presence of osmolytes of which we are aware makes use of partially hydrophobic carboxylic acids with varying alkyl chain lengths (23), and it lends credence to the prediction (20) that TMAO destabilizes hydrophobic contact pair formation. However, there have been no experimental studies involving entirely hydrophobic molecules, nor have there been any experimental studies involving larger collections of hydrophobes.…”

mentioning

confidence: 66%

“…We will refer this cosolute contribution to the free energy as ΔG C→E s . However, one has to consider two other contributions to explain the conformational propensities of PS 20 in the presence of various osmolytes: (i) the gas-phase (or purely intramolecular) contribution to the free-energy difference between collapsed and extended configuration of polystyrene (ΔG C→E gas ) and (ii) the water's contribution to the free-energy difference (ΔG C→E w ), which is not the same in all three solutions since the presence of urea or TMAO will modify the water chemical potential in different ways except at very low-osmolyte concentration. Toward this end, as depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Of particular interest to protein folding models are studies on the effects of osmolytes on hydrophobic interactions, which have primarily been limited to molecular dynamics (MD) simulations (20)(21)(22). The only experimental study on hydrophobic clustering in the presence of osmolytes of which we are aware makes use of partially hydrophobic carboxylic acids with varying alkyl chain lengths (23), and it lends credence to the prediction (20) that TMAO destabilizes hydrophobic contact pair formation.…”

mentioning

confidence: 99%

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How osmolytes influence hydrophobic polymer conformations: A unified view from experiment and theory

Mondal

Halverson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

153

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It is currently the consensus belief that protective osmolytes such as trimethylamine N-oxide (TMAO) favor protein folding by being excluded from the vicinity of a protein, whereas denaturing osmolytes such as urea lead to protein unfolding by strongly binding to the surface. Despite there being consensus on how TMAO and urea affect proteins as a whole, very little is known as to their effects on the individual mechanisms responsible for protein structure formation, especially hydrophobic association. In the present study, we use single-molecule atomic force microscopy and molecular dynamics simulations to investigate the effects of TMAO and urea on the unfolding of the hydrophobic homopolymer polystyrene. Incorporated with interfacial energy measurements, our results show that TMAO and urea act on polystyrene as a protectant and a denaturant, respectively, while complying with Tanford-Wyman preferential binding theory. We provide a molecular explanation suggesting that TMAO molecules have a greater thermodynamic binding affinity with the collapsed conformation of polystyrene than with the extended conformation, while the reverse is true for urea molecules. Results presented here from both experiment and simulation are in line with earlier predictions on a model Lennard-Jones polymer while also demonstrating the distinction in the mechanism of osmolyte action between protein and hydrophobic polymer. This marks, to our knowledge, the first experimental observation of TMAO-induced hydrophobic collapse in a ternary aqueous system. single-molecule force spectroscopy | free energy | preferential binding | TMAO | urea

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Section: Resultssupporting

confidence: 77%

mentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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How osmolytes influence hydrophobic polymer conformations: A unified view from experiment and theory

Mondal

Halverson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

153

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“…Garde and coworkers (19) concluded that TMAO has minimal impact on hydrophobic interactions, but Paul and Patey (20) suggested that TMAO actually weakens hydrophobic forces. Other studies suggested that osmolytes stabilize folded states of proteins indirectly by altering the bulk water structure.…”

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confidence: 99%

Trimethylamine N -oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine

Liao

Manson

DeLyser

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

165

197

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We report experimental and computational studies investigating the effects of three osmolytes, trimethylamine N-oxide (TMAO), betaine, and glycine, on the hydrophobic collapse of an elastin-like polypeptide (ELP). All three osmolytes stabilize collapsed conformations of the ELP and reduce the lower critical solution temperature (LSCT) linearly with osmolyte concentration. As expected from conventional preferential solvation arguments, betaine and glycine both increase the surface tension at the air-water interface. TMAO, however, reduces the surface tension. Atomically detailed molecular dynamics (MD) simulations suggest that TMAO also slightly accumulates at the polymer-water interface, whereas glycine and betaine are strongly depleted. To investigate alternative mechanisms for osmolyte effects, we performed FTIR experiments that characterized the impact of each cosolvent on the bulk water structure. These experiments showed that TMAO red-shifts the OH stretch of the IR spectrum via a mechanism that was very sensitive to the protonation state of the NO moiety. Glycine also caused a red shift in the OH stretch region, whereas betaine minimally impacted this region. Thus, the effects of osmolytes on the OH spectrum appear uncorrelated with their effects upon hydrophobic collapse. Similarly, MD simulations suggested that TMAO disrupts the water structure to the least extent, whereas glycine exerts the greatest influence on the water structure. These results suggest that TMAO stabilizes collapsed conformations via a mechanism that is distinct from glycine and betaine. In particular, we propose that TMAO stabilizes proteins by acting as a surfactant for the heterogeneous surfaces of folded proteins.osmolytes | protein folding | mechanism | spectroscopy | MD simulations M any organisms use small organic osmolytes to stabilize proteins in harsh environments, such as when the salinity is highly variable (1). In particular, trimethylamine N-oxide (TMAO) is known to counteract the denaturing effects of urea as well as salts, and it is present at high concentrations in some aquatic organisms (2). Its effects are often compared with the ions on the left side of the Hofmeister series, which help stabilize the native, folded structures of proteins (Fig. 1).Because of their fundamental biophysical importance, many studies have investigated the behavior and effects of osmolytes. In particular, Timasheff and coworkers (3, 4) proposed that osmolyte effects result from the relative partitioning of these molecules between the bulk solution and the protein-water interface. Stabilization should occur when osmolytes are depleted from the protein-water interface, but proteins will unfold when osmolytes accumulate at this interface. Accordingly, osmolyte effects are often interpreted in terms of an effective protein-water "surface tension." In fact, despite the significant differences between protein surfaces and air-water interfaces, osmolyte effects are often, although not always, consistent with their effect on the air-water interfa...

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Osmolyte Influence on Protein Stability: Perspectives of Theory and Experiment

Rösgen²,

Pettitt

2010

Modeling Solvent Environments

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The Influence of Urea and Trimethylamine-N-oxide on Hydrophobic Interactions

Cited by 63 publications

References 12 publications

How osmolytes influence hydrophobic polymer conformations: A unified view from experiment and theory

How osmolytes influence hydrophobic polymer conformations: A unified view from experiment and theory

Trimethylamine N -oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine

Osmolyte Influence on Protein Stability: Perspectives of Theory and Experiment

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