Correction to Volume Exclusion and H-Bonding Dominate the Thermodynamics and Solvation of Trimethylamine-<i>N</i>-oxide in Aqueous Urea

Rösgen, Jörg; Jackson-Atogi, Ruby

doi:10.1021/ja3056547

Cited by 17 publications

(51 citation statements)

References 4 publications

(6 reference statements)

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“…Early experimental studies by Meersman et al indicated that few TMAO−urea clusters were formed in mixed urea−TMAO solutions; 56 a reanalysis of their data by Rosgen and Jackson-Atogi using an exchange-model now points to stable binding of one urea molecule with TMAO when concentrations of ∼7.5 M urea in 2.5 M TMAO solution are reached. 19 The results from all three force fields show that TMAO forms approximately one stable hydrogen bond with urea (in mixed 8 M urea and 4 M TMAO) and are therefore consistent with the aforementioned experimental results. Interestingly, the total number of hydrogen bonds formed by TMAO with water and urea combined in mixed urea−TMAO solution is very similar to the number of TMAO−water hydrogen bonds formed in pure TMAO solution (approximately three), which further indicates that the loss in the number of TMAO−water hydrogen bonds upon the addition of urea in TMAO solutions is exactly compensated by the formation of the urea−TMAO hydrogen bonds.…”

supporting

confidence: 84%

Hydrophobic Association in Mixed Urea–TMAO Solutions

Ganguly

Vegt

Shea

2016

J. Phys. Chem. Lett.

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The formation of a hydrophobic core is key to the folding and resulting function of most proteins in the cell. In several organisms, as well as in many in vitro experiments, protein folding is modulated by the presence of osmolytes, but the mechanism by which hydrophobic association occurs is not well understood. We present a study of the solvation thermodynamics of hydrophobic self-association in mixed-osmolyte urea-TMAO solutions, with neopentane as a model hydrophobic molecule. Using molecular dynamics simulations and the Kirkwood-Buff theory of solutions, we show that a sensitive balance between the TMAO-water and the TMAO-urea interactions governs the osmolyte-induced changes in hydrophobic association in mixed urea-TMAO solutions. This balance must be correctly incorporated in force-field parametrization because hydrophobic association can be either enhanced or prevented all together by slightly increasing or decreasing the osmolyte-water affinity and osmolyte-osmolyte self-affinity of TMAO molecules.

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confidence: 84%

Hydrophobic Association in Mixed Urea–TMAO Solutions

Ganguly

Vegt

Shea

2016

J. Phys. Chem. Lett.

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“…TMAO, a kosmotrope, locally orders water in our simulations-both the oxide and the methyl moieties of TMAO are hydrated (Fig. 3A)-in agreement with experimental density data (41). Water occupancy (area under curve in absolute units is 0.90 at 0 M vs 1.02 at 1 M) is also enhanced significantly between the methyl groups of the inner and outer TMAO shells (3.5 Å peak in Fig.…”

Section: Resultssupporting

confidence: 88%

TMAO: Protecting Proteins from Feeling the Heat

Boob¹,

Sukenik²,

Gruebele³

et al. 2022

Preprint

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Osmolytes are ubiquitous in the cell and play an important role in controlling protein stability under stress. The natural osmolyte trimethylamine N-oxide (TMAO) is used by marine animals to counteract the effect of pressure denaturation at large depths. The molecular mechanism of TMAO stabilization against pressure and urea denaturation has been extensively studied, but unlike the case of other osmolytes the ability of TMAO to protect proteins from high temperature has not been quantified. To reveal the effect of TMAO on folded and unfolded protein ensembles and the hydration shell at different temperatures, we study a mutant of the well-characterized, fast-folding model protein B (PRB). We carried out >190 µs in total all-atom simulations of thermal folding/unfolding of PRB at multiple temperatures and concentrations of TMAO. The simulations show increased thermal stability of PRB in presence of TMAO. Partly structured, compact ensembles are favored over the unfolded state. TMAO forms two shells near the protein: an outer shell away from the protein surface alters hydrogen bond lifetimes of water molecules and increases hydration of the protein to help stabilize it; a less-populated inner shell with opposite TMAO orientation closer to the protein surface binds exclusively to basic side chains. The cooperative co-solute effect of the inner and outer shell TMAO has a small number of TMAO molecules ‘herding’ water molecules into two hydration shells at or near the protein surface. The stabilizing effect of TMAO on our protein saturates at 1 M despite higher TMAO solubility, so there may be little evolutionary pressure for extremophiles to produce higher intracellular TMAO concentrations if true in general.

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“…Another property which can be used for probing the structural impact of TMAO on the surrounding water is the average number of hydrogen bonds per TMAO molecule as a function of TMAO concentration. Experimental findings based on density and activity coefficient data, 126 dielectric and femtosecond mid-infrared spectroscopy, 127 terahertz/far-infrared absorption measurements, and Raman spectroscopy suggest stable TMAO−water complexes where the TMAO is bound to two, three, or four water molecules. 128 Figure 6 shows the result for the hydrogen bond analysis conducted in this work.…”

Section: The Journal Of Physical Chemistry Bmentioning

confidence: 99%

Validation of Trimethylamine-N-oxide (TMAO) Force Fields Based on Thermophysical Properties of Aqueous TMAO Solutions

et al. 2017

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Five molecular models for trimethylamine N-oxide (TMAO) to be used in conjunction with compatible models for liquid water are evaluated by comparison of molecular dynamics (MD) simulation results to experimental data as functions of TMAO molality. The experimental data comprise thermodynamic properties (density, apparent molar volume, and partial molar volume at infinite dilution), transport properties (self-diffusion and shear viscosity), structural properties (radial distribution functions and degree of hydrogen bonding), and dielectric properties (dielectric spectra and static permittivity). The thermodynamic and transport properties turned out to be useful in TMAO model discrimination while the influence of the water model and the TMAO-water interaction are effectively probed through the calculation of dielectric spectra.

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Correction to Volume Exclusion and H-Bonding Dominate the Thermodynamics and Solvation of Trimethylamine-N-oxide in Aqueous Urea

Cited by 17 publications

References 4 publications

Hydrophobic Association in Mixed Urea–TMAO Solutions

Hydrophobic Association in Mixed Urea–TMAO Solutions

TMAO: Protecting Proteins from Feeling the Heat

Validation of Trimethylamine-N-oxide (TMAO) Force Fields Based on Thermophysical Properties of Aqueous TMAO Solutions

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