Developing Force Fields from the Microscopic Structure of Solutions: The Kirkwood–Buff Approach

Weerasinghe, Samantha; Gee, Moon Bae; Kang, Myungshim; Bentenitis, Nikolaos; Smith, Paul E.

doi:10.1002/9783527629251.ch3

Cited by 20 publications

(49 citation statements)

References 69 publications

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“…83 The C35 force field shows an even more pronounced divergence from ideality, as expected from the higher tendency of its trehalose molecules to self-associate.…”

Section: The Osmotic Pressure Of Aqueous Trehalose Solutions Shows Momentioning

confidence: 94%

Linking Trehalose Self-Association with Binary Aqueous Solution Equation of State

Sapir

Harries

2010

J. Phys. Chem. B

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In aqueous solutions, trehalose possesses a high propensity to form hydrogen bonds with water as well as other trehalose molecules. This hydrogen bonding not only affects water structure but also promotes extensive concentration dependent aggregation of trehalose molecules, which may impact trehalose's role as a protective cosolute to biomacromolecules. To study the association of trehalose in aqueous solutions over a wide concentration range, we used molecular dynamics simulations based on two different force fields, as well as vapor pressure osmometry. By analyzing trehalose cluster size and fractal dimension in simulations, we estimate the cluster percolation threshold at 1.5-2.2 m. Experimentally, trehalose solutions showed positive deviations from ideal van't Hoff's law that grew with concentration. These variations in osmotic pressure can be explained using a simple equation of state that accounts for the repulsive excluded volume interactions between trehalose molecules as well as attractions reflected in sugar clustering. We find that simulations with both applied force fields result in reasonable representations of the solution equation of state. However, in contrast to experiments, the balance between the repulsive and attractive trehalose-trehalose interactions in simulations results in a slightly negative deviation from ideality, probably due to the moderately overaggregative nature of the force fields used.

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“…83 The C35 force field shows an even more pronounced divergence from ideality, as expected from the higher tendency of its trehalose molecules to self-associate.…”

Section: The Osmotic Pressure Of Aqueous Trehalose Solutions Shows Momentioning

confidence: 94%

Linking Trehalose Self-Association with Binary Aqueous Solution Equation of State

Sapir

Harries

2010

J. Phys. Chem. B

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“…33–35 Amino acids were modeled using the AMBER ff99SB-ILDN force field (AMBER) 31–32 in their zwitterionic state, with partial charges determined by Horn; 36 additional simulations were also run using the Kirkwood Buff Force Field (KBFF). 16–18 The full list of amino acids simulated in this study is given in Table 1. TIP3P, 37 TIP4P-Ew, 38 or TIP4P-D 20 water models were used with the AMBER protein force field, while the SPC/E 39 water model was used with the KBFF.…”

Section: Methodsmentioning

confidence: 99%

“…A somewhat different approach has been taken by the Smith group, which has pioneered the use of Kirkwood Buff Integrals 15 (KBIs) as a means of connecting simulated and experimental thermodynamics over a wide range of solute concentrations, and has used KBIs calculated for a number of sidechain analogs as a basis for developing a general protein force field, KBFF. 16–18 …”

Section: Introductionmentioning

confidence: 99%

Osmotic Pressure Simulations of Amino Acids and Peptides Highlight Potential Routes to Protein Force Field Parameterization

2016

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Recent molecular dynamics (MD) simulations of proteins have suggested that common force fields overestimate the strength of amino acid interactions in aqueous solution. In an attempt to determine the causes of these effects, we have measured the osmotic coefficients of a number of amino acids using the AMBER ff99SB-ILDN force field with two popular water models, and compared the results with available experimental data. With TIP4P-Ew water, interactions between aliphatic residues agree well with experiment, but interactions of the polar residues serine and threonine are found to be excessively attractive. For all tested amino acids, the osmotic coefficients are lower when the TIP3P water model is used. Additional simulations performed on charged amino acids indicate that the osmotic coefficients are strongly dependent on the parameters assigned to the salt ions, with a reparameterization of the sodium:carboxylate interaction reported by the Aksimentiev group significantly improving description of the osmotic coefficient for glutamate. For five neutral amino acids, we also demonstrate a decrease in solute-solute attractions using the recently reported TIP4P-D water model and using the KBFF force field. Finally, we show that for four two-residue peptides improved agreement with experiment can be achieved by re-deriving the partial charges for each peptide.

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“…2B) were simulated using classical MD techniques and the GROMACS simulation package (version 4.0) 19 in the isothermal-isobaric ( NpT ) ensemble at a p of 1.0 atm and a T of 303.15 K in 0.15 M NaCl using the v-rescale thermostat 20 and the Berendsen barostat 21 , with relaxation times of 0.1 ps and 5.0 ps, respectively, with a 4.5 × 10 −5 bar −1 compressibility. The protein and ions were modeled using the Kirkwood-Buff Force Field (KBFF.chem.k-state.edu) 22,23 in explicit solvent with the SPC/E water model. 24 Truncated octahedron boxes defined the systems.…”

Section: Methodsmentioning

confidence: 99%

Flexible connection of the N‐terminal domain in ClpB modulates substrate binding and the aggregate reactivation efficiency

et al. 2012

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ClpB reactivates aggregated proteins in cooperation with DnaK/J. The ClpB monomer contains two nucleotide-binding domains (D1, D2), a coiled-coil domain, and an N-terminal domain attached to D1 with a 17-residue-long unstructured linker containing a Gly-Gly motif. The ClpB-mediated protein disaggregation is linked to translocation of substrates through the central channel in the hexameric ClpB, but the events preceding the translocation are poorly understood. The N-terminal domains form a ring surrounding the entrance to the channel and contribute to the aggregate binding. It was suggested that the N-terminal domain’s mobility that is maintained by the unstructured linker might control the efficiency of aggregate reactivation. We produced seven variants of ClpB with modified sequence of the N-terminal linker. To increase the linker’s conformational flexibility, we inserted up to four Gly next to the GG motif. To decrease the linker’s flexibility, we deleted the GG motif and converted it into GP and PP. We found that none of the linker modifications inhibited the basal ClpB ATPase activity or its capability to form oligomers. However, the modified linker ClpB variants showed lower reactivation rates for aggregated glucose-6-phosphate dehydrogenase and firefly luciferase and a lower aggregate-binding efficiency than wt ClpB. We conclude that the linker does not merely connect the N-terminal domain, but it supports the chaperone activity of ClpB by contributing to the efficiency of aggregate binding and disaggregation. Moreover, our results suggest that selective pressure on the linker sequence may be crucial for maintaining the optimal efficiency of aggregate reactivation by ClpB.

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Developing Force Fields from the Microscopic Structure of Solutions: The Kirkwood–Buff Approach

Cited by 20 publications

References 69 publications

Linking Trehalose Self-Association with Binary Aqueous Solution Equation of State

Linking Trehalose Self-Association with Binary Aqueous Solution Equation of State

Osmotic Pressure Simulations of Amino Acids and Peptides Highlight Potential Routes to Protein Force Field Parameterization

Flexible connection of the N‐terminal domain in ClpB modulates substrate binding and the aggregate reactivation efficiency

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