Theory and Simulation of Multicomponent Osmotic Systems

Karunaweera, Sadish; Gee, Moon Bae; Weerasinghe, Samantha; Smith, Paul E.

doi:10.1021/ct300079v

Cited by 24 publications

(88 citation statements)

References 57 publications

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“…As was the case with single amino acids (Figure 5A), the KBFF produced the highest osmotic coefficients, even though our computed value for Gly-Gly (ϕ = 0.83) is somewhat lower than that previously reported by the Smith group (ϕ = 0.88). 53 …”

Section: Resultsmentioning

confidence: 99%

“…These include reports from the Roux group, 47 whose protocol we have followed closely here, the Aksimentiev 42, 76 , Smith 53 and Mackerell 77 groups, as well as work on carbohydrates from our own group. 78 The principal results of this study are as follows: (a) the combination of AMBER + TIP4P-Ew produces excellent osmotic coefficients for the neutral amino acids Ala, Gly, Pro and Val (the latter at 1 M) but noticeably underestimates the osmotic coefficients of the hydroxyl-containing amino acids Ser and Thr, (b) the osmotic coefficients obtained with TIP3P are uniformly lower than those obtained with TIP4P-Ew, which, in turn, are much lower than those obtained with the newly developed TIP4P-D water model, (c) the osmotic coefficients of the charged amino acids Arg, Glu, Hip and Lys are sensitive to the parameters assigned to the neutralizing counterion, and the poor agreement obtained with the original Joung & Cheatham parameters for Na-Glu is almost entirely corrected by the modification proposed by Yoo & Aksimentiev, 42 (d) the osmotic coefficients of the four two-residue peptides tested here are much too low when using the original AMBER charges with TIP4P-Ew water but are in good agreement with experiment when simulations are run with partial charges derived specifically for each peptide.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

2016

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“…(Such derivatives have been studied from a KB-based perspective, but under different experimental conditions and thermodynamic constraints. 45,46 ) This can be executed both for inhomogeneous (Appendix B) and homogeneous (Appendix C) solutions, both of which will yield the same result (Appendix C). For the sake of clarity, we present the following expression for the inhomogeneous solution: …”

Section: Origin Of the Minimum Hydrotropementioning

confidence: 99%

Hydrotropy: Monomer–Micelle Equilibrium and Minimum Hydrotrope Concentration

2014

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Drug molecules with low aqueous solubility can be solubilized by a class of cosolvents, known as hydrotropes. Their action has often been explained by an analogy with micelle formation, which exhibits critical micelle concentration (CMC). Indeed, hydrotropes also exhibit "minimum hydrotrope concentration" (MHC), a threshold concentration for solubilization. However, MHC is observed even for nonaggregating monomeric hydrotropes (such as urea); this raises questions over the validity of this analogy. Here we clarify the effect of micellization on hydrotropy, as well as the origin of MHC when micellization is not accompanied. On the basis of the rigorous Kirkwood-Buff (KB) theory of solutions, we show that (i) micellar hydrotropy is explained also from preferential drug-hydrotrope interaction; (ii) yet micelle formation reduces solubilization effeciency per hydrotrope molecule; (iii) MHC is caused by hydrotrope-hydrotrope self-association induced by the solute (drug) molecule; and (iv) MHC is prevented by hydrotrope self-aggregation in the bulk solution. We thus need a departure from the traditional view; the structure of hydrotrope-water mixture around the drug molecule, not the structure of the aqueous hydrotrope solutions in the bulk phase, is the true key toward understanding the origin of MHC.

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“…In the first, 15 the Smith group used osmotic pressures to validate the self-interactions of Glycine (Gly) modeled using their Kirkwood-Buff derived force field. 16–18 In the second, 7 Yoo and Aksimentiev simulated the self-interactions of Gly in water and found them to be too favorable using both the AMBER and CHARMM force fields.…”

Section: Introductionmentioning

confidence: 99%

Reparametrization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements from Molecular Dynamics Simulations

Miller

Lay

et al. 2017

J. Chem. Theory Comput.

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There is a small, but growing, body of literature describing the use of osmotic coefficient measurements to validate and reparameterize simulation force fields. Here we have investigated the ability of five very commonly used force field and water model combinations to reproduce the osmotic coefficients of seven neutral amino acids and five small molecules. The force fields tested include AMBER ff99SB-ILDN, CHARMM36, GROMOS54a7, and OPLS-AA, with the first of these tested in conjunction with the TIP3P and TIP4P-Ew water models. In general, for both the amino acids and the small molecules, the tested force fields produce computed osmotic coefficients that are lower than experiment; this is indicative of excessively favorable solute-solute interactions. The sole exception to this general trend is provided by GROMOS54a7 when applied to amino acids: in this case, the computed osmotic coefficients are consistently too high. Importantly, we show that all of the force fields tested can be made to accurately reproduce the experimental osmotic coefficients of the amino acids when minor modifications – some previously reported by others and some that are new to this study – are made to the van der Waals interactions of the charged terminal groups. Special care is required, however, when simulating Proline with a number of the force fields, and a hydroxyl-group specific modification is required in order to correct Serine and Threonine when simulated with AMBER ff99SB-ILDN. Interestingly, an alternative parameterization of the van der Waals interactions in the latter force field, proposed by the Nerenberg and Head-Gordon groups, is shown to immediately produce osmotic coefficients that are in excellent agreement with experiment. Overall, this study reinforces the idea that osmotic coefficient measurements can be used to identify general shortcomings in commonly used force fields’ descriptions of solute-solute interactions, and further demonstrates that modifications to van der Waals parameters provides a simple route to optimizing agreement with experiment.

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Theory and Simulation of Multicomponent Osmotic Systems

Cited by 24 publications

References 57 publications

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

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

Hydrotropy: Monomer–Micelle Equilibrium and Minimum Hydrotrope Concentration

Reparametrization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements from Molecular Dynamics Simulations

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