Kirkwood–Buff-Derived Force Field for Peptides and Proteins: Philosophy and Development of KBFF20

Ploetz, Elizabeth A.; Karunaweera, Sadish; Bentenitis, Nikolaos; Chen, Feng; Dai, Shixun; Gee, Moon Bae; Jiao, Yuanfang; Kang, Myungshim; Kariyawasam, Nilusha L.; Naleem, Nawavi; Weerasinghe, Samantha; Smith, Paul E.

doi:10.1021/acs.jctc.1c00075

Cited by 21 publications

(36 citation statements)

References 234 publications

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“…32 This would be consistent with our Gly Ramachandran maps being too biased to the α region. However, as noted previously, 1 Pappu has suggested that these peptides were studied under high enough concentration that effects due to Correlation between experimental and simulated J-coupling constants for small peptides. The letters refer to the coupling type/angle using the following classification: a is 3…”

Section: ■ Resultsmentioning

confidence: 82%

“…In the first of this two-part study, we reported the philosophy behind, and subsequent development of, a Kirkwood−Buffderived force field (FF), KBFF20, for the simulation of peptides and proteins. 1 Here, we present results for the simulation of a variety of peptide and protein systems using KBFF20 and compare them to a variety of experimental data sets. In addition, we also provide some perspective for how well these results are compared to those of alternative early and modern class I FFs for the simulation of biomolecules in explicit solvent.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The KBFF20 philosophy and development paper quantified the residue-based Ramachandran region populations of all of the amino acid residues based on the simulation of blocked tripeptides, Ac-AXA-NHM, where Ac is the acetyl group and NHM is the name of the N− H methyl group. 1 Unfortunately, the experimental populations are unknown for these systems. Thus, a natural first test is the determination of NMR-derived J-coupling constants for small peptides, which historically have been used to test for imbalances in FF backbone potentials because they inform on the backbone dihedral angles.…”

Section: ■ Introductionmentioning

confidence: 99%

“…15 It would have been desirable to study other additional oligopeptides. Therefore, we sought to find the experimental radius of gyration data for polyglycine, polyglutamine (our representative amino acid 1 ), and polyproline. However, all three systems were subsequently rejected.…”

Section: ■ Introductionmentioning

confidence: 99%

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Kirkwood–Buff-Derived Force Field for Peptides and Proteins: Applications of KBFF20

Ploetz

Karunaweera

Smith

2021

J. Chem. Theory Comput.

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Here, we perform structural, thermodynamic, and kinetics tests of the Kirkwood–Buff-derived force field, KBFF20, for peptides and proteins developed in the previous article. The physical/structural tests measure the ability of KBFF20 to capture the experimental J-couplings for small peptides, to keep globular monomeric and oligomeric proteins folded, and to produce the experimentally relevant expanded conformational ensembles of intrinsically disordered proteins. The thermodynamic-based tests probe KBFF20’s ability to quantify the preferential interactions of sodium chloride around native β-lactoglobulin and urea around native lysozyme, to reproduce the melting curves for small helix- and sheet-based peptides, and to fold the small proteins Trp-cage and Villin. The kinetics-based tests quantify how well KBFF20 can match the experimental contact formation rates of small, repeat-sequence peptides of variable lengths and the rotational diffusion coefficients of globular proteins. The results suggest that KBFF20 is naturally able to reproduce properties of both folded and disordered proteins, which we attribute to the use of the Kirkwood–Buff theory as the foundation of the force field’s development. However, we show that KBFF20 tends to lose some well-defined secondary structural elements and increases the percentage of coil regions, indicating that the perfect balance of all interactions remains elusive. Nevertheless, we argue that KBFF20 is an improvement over recently modified force fields that require ad hoc interventions to prevent the collapse of intrinsically disordered proteins.

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Section: ■ Resultsmentioning

confidence: 82%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Kirkwood–Buff-Derived Force Field for Peptides and Proteins: Applications of KBFF20

Ploetz

Karunaweera

Smith

2021

J. Chem. Theory Comput.

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“…Their efforts have focused on adjusting charge parameters, along with some LJ parameters, to match Kirkwood-Buff integral values and better capture solute-solvent interactions. This method has been used to parameterize a wide range of systems, from simple systems [35] to a complete protein and peptide force field [38].…”

Section: Introductionmentioning

confidence: 99%

Improving force field accuracy by training against condensed phase mixture properties

Boothroyd

Madin

Mobley

et al. 2022

Preprint

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Developing a sufficiently accurate classical force field representation of molecules is key to realizing the full potential of molecular simulation as a route to gaining fundamental insight into a broad spectrum of chemical and biological phenomena. This is only possible, however, if the many complex interactions between molecules of different species in the system are accurately captured by the model. Historically, the intermolecular van der Waals (vdW) interactions have primarily been trained against densities and enthalpies of vaporization of pure (single-component) systems, with occasional usage of hydration free energies. In this study, we demonstrate how including physical property data of binary mixtures can better inform these parameters, encoding more information about the underlying physics of the system in complex chemical mixtures. To demonstrate this, we re-train a select number of the Lennard-Jones parameters describing the vdW interactions of the OpenFF 1.0.0 (Parsley) fixed charge force field against training sets composed of densities and enthalpies of mixing for binary liquid mixtures as well as densities and enthalpies of vaporization of pure liquid systems, and assess the performance of each of these combinations. We show that retraining against the mixture data almost universally improves the force field's ability to reproduce both pure and mixture properties, reducing some systematic errors that exist when training vdW interactions against properties of pure systems only.

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The intrinsically disordered transcriptional activation domain of CIITA is functionally tuneable by single substitutions: An exception or a new paradigm?

Sreenivasan,

Heffren,

Suh

et al. 2024

Protein Science

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During protein evolution, some amino acid substitutions modulate protein function (“tuneability”). In most proteins, the tuneable range is wide and can be sampled by a set of protein variants that each contains multiple amino acid substitutions. In other proteins, the full tuneable range can be accessed by a set of variants that each contains a single substitution. Indeed, in some globular proteins, the full tuneable range can be accessed by the set of site‐saturating substitutions at an individual “rheostat” position. However, in proteins with intrinsically disordered regions (IDRs), most functional studies – which would also detect tuneability – used multiple substitutions or small deletions. In disordered transcriptional activation domains (ADs), studies with multiple substitutions led to the “acidic exposure” model, which does not anticipate the existence of rheostat positions. In the few studies that did assess effects of single substitutions on AD function, results were mixed: The ADs of two full‐length transcription factors did not show tuneability, whereas a fragment of a third AD was tuneable by single substitutions. Here, we tested tuneability in the AD of full‐length human class II transactivator (CIITA). Sequence analyses and experiments showed that CIITA's AD is an IDR. Functional assays of singly‐substituted AD variants showed that CIITA's function was highly tuneable, with outcomes not predicted by the acidic exposure model. Four tested positions showed rheostat behaviour for transcriptional activation. Thus, tuneability of different IDRs can vary widely. Future studies are needed to illuminate the biophysical features that govern whether an IDR is tuneable by single substitutions.This article is protected by copyright. All rights reserved.

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Kirkwood–Buff-Derived Force Field for Peptides and Proteins: Philosophy and Development of KBFF20

Cited by 21 publications

References 234 publications

Kirkwood–Buff-Derived Force Field for Peptides and Proteins: Applications of KBFF20

Kirkwood–Buff-Derived Force Field for Peptides and Proteins: Applications of KBFF20

Improving force field accuracy by training against condensed phase mixture properties

The intrinsically disordered transcriptional activation domain of CIITA is functionally tuneable by single substitutions: An exception or a new paradigm?

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