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

Miller, Mark S.; Lay, Wesley K.; Elcock, Adrian H.

doi:10.1021/acs.jpcb.6b01902

Cited by 29 publications

(100 citation statements)

References 77 publications

(205 reference statements)

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“…server utilities 47 with AMBERTools11 48 as described in our previous study (see below). 19 For the six natural amino acids in CHARMM, GROMOS, and OPLS-AA, partial charges and vdW parameters were given directly by the force field; for αABA, partial charges were assigned by analogy using Val as a reference compound. Parameter files for αABA can be found in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

“…Here we have tested the extent to which these proposed modifications also improve the behavior of other amino acids. In the cases of Ser and Thr with the AMBER force field, which we have previously shown to produce anomalously low osmotic coefficients, 19 we carried out a second set of simulations in which the Gly modification was supplemented with an identical increase to the σ value for interactions of the hydroxyl oxygen (OH) with both the amino nitrogen and carboxylate oxygen atoms (see Results). Finally, in the case of Pro, which in contrast to the other amino acids contains a secondary amine, we performed simulations both with and without the modification proposed by the Aksimentiev group (see Results).…”

Section: Methodsmentioning

confidence: 99%

“…79 However, we further tested this assumption for t-butanol by calculating γ i m using molar concentrations calculated directly from density data 80 (yellow squares in Figure S4A; see below). In the second stage, the computed γ m values were converted to osmotic coefficients as in our previous work 19 by plotting molality versus ln(γ m ) and integrating using the Trapezoid rule, described by Hamer, 81 up to the concentration of interest.…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, they then dramatically improved the agreement with experiment by making subtle adjustments to the van der Waals (vdW) terms describing interactions of the charged amino and carboxyl groups. In the third study, 19 we calculated osmotic coefficients for a variety of amino acids using the AMBER ff99SB-ILDN 20 force field in combination with three different water models. We found the osmotic coefficients to be sensitive to the water model used and showed that, while the interactions of aliphatic amino acids were in very good agreement with experiment when simulated with the TIP4P-Ew water model, the interactions of amino acids containing hydroxyl groups (Ser, Thr) were too favorable.…”

Section: Introductionmentioning

confidence: 99%

“…We also use the same force fields to measure the osmotic coefficients for five small molecules containing hydroxyl, amide, and aromatic functional groups, whose interactions we suspected in our earlier work 19 were likely to be too favorable. Our results indicate that excessively favorable solute-solute interactions are likely to be a common, but not universal, feature of each of the tested force fields and suggest that reparameterization of the interactions of certain types of functional group (e.g.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Improved model of hydrated calcium ion for molecular dynamics simulations using classical biomolecular force fields

2016

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Calcium ions (Ca2+) play key roles in various fundamental biological processes such as cell signaling and brain function. Molecular dynamics (MD) simulations have been used to study such interactions, however, the accuracy of the Ca2+ models provided by the standard MD force fields has not been rigorously tested. Here, we assess the performance of the Ca2+ models from the most popular classical force fields AMBER and CHARMM by computing the osmotic pressure of model compounds and the free energy of DNA–DNA interactions. In the simulations performed using the two standard models, Ca2+ ions are seen to form artificial clusters with chloride, acetate, and phosphate species; the osmotic pressure of CaAc2 and CaCl2 solutions is a small fraction of the experimental values for both force fields. Using the standard parameterization of Ca2+ ions in the simulations of Ca2+-mediated DNA–DNA interactions leads to qualitatively wrong outcomes: both AMBER and CHARMM simulations suggest strong inter-DNA attraction whereas, in experiment, DNA molecules repel one another. The artificial attraction of Ca2+ to DNA phosphate is strong enough to affect the direction of the electric field-driven translocation of DNA through a solid-state nanopore. To address these shortcomings of the standard Ca2+ model, we introduce a custom model of a hydrated Ca2+ ion and show that using our model brings the results of the above MD simulations in quantitative agreement with experiment. Our improved model of Ca2+ can be readily applied to MD simulations of various biomolecular systems, including nucleic acids, proteins and lipid bilayer membranes.

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How to strike a conformational balance in protein force fields for molecular dynamics simulations?

Kang

Jiang

2021

WIREs Comput Mol Sci

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Molecular dynamics (MD) simulation is a powerful tool for exploring the conformational energy landscape of proteins, and the reliability of MD results is crucially dependent on the underlying force field (FF). An accurate FF capable of producing balanced distributions of diverse conformations at multiple levels has been a long‐sought goal. Towards this, several decades of joint efforts have been made to address FF deficiencies, manifested by conformational biases at different levels (local conformations, secondary structures, and global extendedness of polypeptide chain). We first present the major FF biases, then review the strategies to address them separately. Specifically, both nonresidue‐specific and residue‐specific strategies for torsional parameter optimization have been applied to achieve local conformation and secondary structure balances. Significant improvements can be gained with residue‐specific torsional parameters especially when explicit dihedral couplings are considered. Further, the additional balance between protein–protein and protein–water interactions has been optimized via multiple ways to reproduce the global extendedness of polypeptide chains, especially for unfolded or disordered proteins. This review aims to summarize the most valuable experience and lessons gained from the past, which, we hope, can facilitate further improvements of both classical FFs and more sophisticated models such as polarizable FFs. This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Molecular and Statistical Mechanics > Molecular Mechanics

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

Cited by 29 publications

References 77 publications

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

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

Improved model of hydrated calcium ion for molecular dynamics simulations using classical biomolecular force fields

How to strike a conformational balance in protein force fields for molecular dynamics simulations?

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