Preferential Solvation in Urea Solutions at Different Concentrations:  Properties from Simulation Studies

Kokubo, Hironori; Pettitt, B. Montgomery

doi:10.1021/jp067659x

Cited by 91 publications

(126 citation statements)

References 36 publications

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“…The association of the water-hydrogen to the urea-oxygen also brings the water-oxygen close to the urea-oxygen as indicated by the corresponding peak in urea-oxygen and water-oxygen curve. 29 In Figure 4(b), we show the RDFs between TMAO and water. The TMAO-oxygen to waterhydrogen peak probability occurs at a close distance (again at less than 2.0Å ) indicating strong hydrogen bonding.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

Backbone additivity in the transfer model of protein solvation

et al. 2010

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“…Similar H-bonding at both peptide NH and carbonyl sites is reasonable because urea is a very good H-bond donor and acceptor. Urea readily incorporates into the H-bonded network of water and H-bonds equally well with other urea molecules (49)(50)(51)(52)(53). Some MD simulations indicate that urea aggregates in preference to urea-water interaction, but this appears to be an Table 1.…”

Section: Discussionmentioning

confidence: 99%

Urea, but not guanidinium, destabilizes proteins by forming hydrogen bonds to the peptide group

Lim

Rösgen

Englander

2009

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

360

370

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The mechanism by which urea and guanidinium destabilize protein structure is controversial. We tested the possibility that these denaturants form hydrogen bonds with peptide groups by measuring their ability to block acid-and base-catalyzed peptide hydrogen exchange. The peptide hydrogen bonding found appears sufficient to explain the thermodynamic denaturing effect of urea. Results for guanidinium, however, are contrary to the expectation that it might H-bond. Evidently, urea and guanidinium, although structurally similar, denature proteins by different mechanisms.denaturation ͉ hydrogen exchange ͉ osmolyte ͉ solvation B ecause of its fundamental importance, the study of protein molecular stability has engaged the attention of protein chemists for the last 100 years (1, 2). Experimental and theoretical investigations of protein stability have often focused on small-molecule osmolytes that can be used to modulate stability in vitro (3-6) and are used by virtually all organisms to counter biochemical stress in vivo (7). The mechanism of osmolyte action continues to be controversial. Opposing positions favor either a direct interaction between protein and osmolyte (8-11), such as hydrogen bonding, or an indirect effect mediated by the alteration of water structure (12, 13), or a mixture of both (14)(15)(16)(17)(18)(19). It has been difficult to distinguish between these direct and indirect models because the osmolyte-protein interaction is so weak.It is a thermodynamic truism (20-22) that the concentration of destabilizing osmolytes must be enriched relative to water molecules in the vicinity of the protein surface that becomes newly exposed upon unfolding (preferential interaction). In a thermodynamic sense, denaturing osmolytes ''bind'' selectively to the increased surface of unfolded proteins and thus bias the folded/ unfolded equilibrium toward denaturation. Similarly, stabilizing osmolytes must be preferentially excluded from the protein surface. This is true independently of the physical mechanism of the ''binding'' or ''antibinding'' interaction. Thermodynamically based studies directed at the binding/antibinding problem have been designed to measure the transfer free energy of the various component groups of proteins between water and osmolyte solutions. Results show that the main-chain peptide group makes the largest contribution to the energetics, accounting for Ϸ80% of the effect of urea and of strong stabilizers such as trimethyl amine N-oxide (TMAO) (23). Similar determinations for guanidinium are not yet available, but it seems clear that guanidinium also favorably interacts with the peptide group (8,11,24).To search for the mechanistic basis of thermodynamic destabilization due to urea and guanidinium, we tested the possibility that they exert their denaturing effect through peptide group hydrogen bonding. This can be done experimentally by the straightforward measurement of acid-and base-catalyzed hydrogen exchange (HX) in a small-molecule peptide model. Osmolyte that is H-bonded to the peptide NH ...

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“…Such a large simulation box was suggested previously to allow the tails of RDFs to converge properly therefore minimizing possible long-range effects when calculating KBIs. 10 The systems, using the additive model, were then simulated to allow for extensive equilibration. RDFs were monitored to make sure that they became stable with increased simulation time, indicating that the solutions were fully mixed at the end of equilibration (usually about 1 ns).…”

Section: Methodsmentioning

confidence: 99%

“…In the past decade, interest in understanding the properties of liquid mixtures has been steadily growing, leading to a number of computer simulations of the properties of liquid mixtures. [3][4][5][6][7][8][9][10][11] Two ingredients are required to clarify the relationship between the molecular details of liquid mixtures and the macroscopic properties using computer simulations. The first is an exact molecular theory of liquid mixtures to formally link the macroscopic properties to the underlying microscopic details of the system.…”

Section: Introductionmentioning

confidence: 99%

Kirkwood-Buff analysis of aqueous N-methylacetamide and acetamide solutions modeled by the CHARMM additive and Drude polarizable force fields

Lin

Lopes

Roux

et al. 2013

The Journal of Chemical Physics

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Kirkwood-Buff analysis was performed on aqueous solutions of N-methylacetamide and acetamide using the Chemistry at HARvard Molecular Mechanics additive and Drude polarizable all-atom force fields. Comparison of a range of properties with experimental results, including Kirkwood-Buff integrals, excess coordination numbers, solution densities, partial molar values, molar enthalpy of mixing, showed both models to be well behaved at higher solute concentrations with the Drude model showing systematic improvement at lower solution concentrations. However, both models showed difficulties reproducing experimental activity derivatives and the excess Gibbs energy, with the Drude model performing slightly better. At the molecular level, the improved agreement of the Drude model at low solute concentrations is due to increased structure in the solute-solute and solute-solvent interactions. The present results indicate that the explicit inclusion of electronic polarization leads to improved modeling of dilute solutions even when those properties are not included as target data during force field optimization.

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Preferential Solvation in Urea Solutions at Different Concentrations: Properties from Simulation Studies

Cited by 91 publications

References 36 publications

Backbone additivity in the transfer model of protein solvation

Backbone additivity in the transfer model of protein solvation

Urea, but not guanidinium, destabilizes proteins by forming hydrogen bonds to the peptide group

Kirkwood-Buff analysis of aqueous N-methylacetamide and acetamide solutions modeled by the CHARMM additive and Drude polarizable force fields

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