@article {2015|1755,
	title = {How osmolytes influence hydrophobic polymer conformations: A unified view from experiment and theory.},
	journal = {Proc. Natl. Acad. Sci. Usa},
	volume = {112},
	year = {2015},
	pages = {9270{\textendash}5},
	abstract = {<p>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.</p>},
	keywords = {Atomic Force, Computer Simulation, Hydrophobic and Hydrophilic Interactions, Mechanical, Methylamines, Methylamines: chemistry, Microscopy, Molecular Dynamics Simulation, Normal Distribution, Polymers, Polymers: chemistry, Polystyrenes, Polystyrenes: chemistry, Protein Binding, Protein Conformation, Protein Folding, Proteins, Proteins: chemistry, Software, Solvents, Solvents: chemistry, Stress, Thermodynamics, Urea, Urea: chemistry, Water, Water: chemistry},
	isbn = {1215421109},
	issn = {1091-6490},
	doi = {10.1073/pnas.1511780112},
	url = {http://www.pnas.org/content/112/30/9270},
	author = {Mondal, Jagannath and Halverson, Duncan and Li, Isaac T S and Guillaume Stirnemann and Walker, Gilbert C and Berne, Bruce J}
}
@article {2013|1689,
	title = {When Does Trimethylamine <italic>N</italic>-Oxide Fold a Polymer Chain and Urea Unfold It?},
	journal = {J. Phys. Chem. B},
	volume = {117},
	year = {2013},
	pages = {8723{\textendash}8732},
	abstract = {<p>Longstanding mechanistic questions about the role of protecting osmolyte trimethylamine N-oxide (TMAO) that favors protein folding and the denaturing osmolyte urea are addressed by studying their effects on the folding of uncharged polymer chains. Using atomistic molecular dynamics simulations, we show that 1 M TMAO and 7 M urea solutions act dramatically differently on these model polymer chains. Their behaviors are sensitive to the strength of the attractive dispersion interactions of the chain with its environment: when these dispersion interactions are sufficiently strong, TMAO suppresses the formation of extended conformations of the hydrophobic polymer as compared to water while urea promotes the formation of extended conformations. Similar trends are observed experimentally for real protein systems. Quite surprisingly, we find that both protecting and denaturing osmolytes strongly interact with the polymer, seemingly in contrast with existing explanations of the osmolyte effect on proteins. We show that what really matters for a protective osmolyte is its effective depletion as the polymer conformation changes, which leads to a negative change in the preferential binding coefficient. For TMAO, there is a much more favorable free energy of insertion of a single osmolyte near collapsed conformations of the polymer than near extended conformations. By contrast, urea is preferentially stabilized next to the extended conformation and thus has a denaturing effect.</p>},
	isbn = {15206106},
	url = {http://pubs.acs.org/doi/abs/10.1021/jp405609j$\backslash$nhttp://pubs.acs.org/doi/pdf/10.1021/jp405609j$\backslash$nhttp://dx.doi.org/10.1021/jp405609j},
	author = {Mondal, Jagannath and Guillaume Stirnemann and Berne, B J}
}
