Binary Phases of Aliphatic <i>N</i>-Oxides and Water:  Force Field Development and Molecular Dynamics Simulation

Kast, Kristine M.; Brickmann, Jürgen; Kast, Stefan M.; Berry, R. Stephen

doi:10.1021/jp027336a

Cited by 136 publications

(193 citation statements)

References 54 publications

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“…In the following calculations, we described water with the extended simple-point charge model (SPC/E) (32) and TMAO with the popular model by Kast and coworkers (33). We modeled both the ELP fragment and glycine with the CHARMM27 force field (34) while using the correction map (CMAP) (35).…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…55 The TMAO parameters were obtained from previously published results. 56 For the pure water solutions, 1778 water molecules in a solvation box with 3.8 nm side lengths were used.…”

Section: Discussionmentioning

confidence: 99%

Backbone additivity in the transfer model of protein solvation

et al. 2010

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The transfer model implying additivity of the peptide backbone free energy of transfer is computationally tested. Molecular dynamics simulations are used to determine the extent of change in transfer free energy (DG tr ) with increase in chain length of oligoglycine with capped end groups. Solvation free energies of oligoglycine models of varying lengths in pure water and in the osmolyte solutions, 2M urea and 2M trimethylamine N-oxide (TMAO), were calculated from simulations of all atom models, and DG tr values for peptide backbone transfer from water to the osmolyte solutions were determined. The results show that the transfer free energies change linearly with increasing chain length, demonstrating the principle of additivity, and provide values in reasonable agreement with experiment. The peptide backbone transfer free energy contributions arise from van der Waals interactions in the case of transfer to urea, but from electrostatics on transfer to TMAO solution. The simulations used here allow for the calculation of the solvation and transfer free energy of longer oligoglycine models to be evaluated than is currently possible through experiment. The peptide backbone unit computed transfer free energy of 254 cal/mol/M compares quite favorably with 243 cal/mol/M determined experimentally.

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“…18,19 and ref. 20 for a recent review), designing adequate forcefields [21][22][23][24][25][26] and investigating its interactions with model polymers 25,[27][28][29][30] and proteins.…”

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confidence: 99%

“…41 BornOppenheimer molecular dynamics simulations were performed in the canonical ensemble: the temperature was controlled using a Nose-Hoover thermostat, and the density was fixed at its extrapolated experimental value. 33 Systems were first equilibrated via classical MD simulations using a classical TMAO forcefield 21 and the SPC/E water model. 42 The dilute solution Simulations were performed for 80 ps for the dilute solution at 323 K and the concentrated solution at 300 K, whereas the dilute solution at 300 K was simulated for 160 ps.…”

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confidence: 99%

Ab Initio Simulations of Water Dynamics in Aqueous TMAO Solutions: Temperature and Concentration Effects

2017

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We use ab initio molecular dynamics simulation to study the effect of hydrophobic groups on the dynamics of water molecules in aqueous solutions of trimethylamine N-oxide. We show that hydrophobic groups induce a moderate (< 2-fold) slowdown of water reorientation and hydrogen-bond dynamics in dilute solutions, but that this slowdown rapidly increases with solute concentration. In addition, the slowdown factor is found to vary very little with temperature, thus suggesting an entropic origin. All these results are in quantitative agreement with prior classical molecular dynamics simulations and with the previously suggested excluded-volume model. The hydrophilic TMAO headgroup is found to affect water dynamics more strongly than the hydrophobic moiety, and the magnitude of this slowdown is very sensitive to the strength of the water-solute hydrogen-bond.

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Binary Phases of Aliphatic N-Oxides and Water: Force Field Development and Molecular Dynamics Simulation

Cited by 136 publications

References 54 publications

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

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

Backbone additivity in the transfer model of protein solvation

Ab Initio Simulations of Water Dynamics in Aqueous TMAO Solutions: Temperature and Concentration Effects

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