Coupled binding–bending–folding: The complex conformational dynamics of protein-DNA binding studied by atomistic molecular dynamics simulations

Vaart, Arjan van der

doi:10.1016/j.bbagen.2014.08.009

Cited by 29 publications

(37 citation statements)

References 183 publications

(209 reference statements)

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“…Classical, fixed-charge force fields for biomolecules in water have been under evolution for decades and are now quite successful at predicting binding affinities 6 and the folded structure of small proteins, 7-9 the self-assembly of phospholipid bilayers, 10 the importance of electrostatics in DNA, and DNA-protein interactions. 11,12 These force fields were parameterized against experimental observables that reflect the balance between ionwater, biomolecule-water and water-water interactions (e.g., free energies of hydration). 13,14 More recently, force fields for aqueous solutions of alkali, alkali-earth and halide ions were developed that also show reasonable anion-cation interactions.…”

Section: Introductionmentioning

confidence: 99%

Developing force fields when experimental data is sparse: AMBER/GAFF-compatible parameters for inorganic and alkyl oxoanions

Kashefolgheta

Verde

2017

Phys. Chem. Chem. Phys.

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We present a set of Lennard-Jones parameters for classical, all-atom models of acetate and various alkylated and non-alkylated forms of sulfate, sulfonate and phosphate ions, optimized to reproduce their interactions with water and with the physiologically relevant sodium, ammonium and methylammonium cations. The parameters are internally consistent and are fully compatible with the Generalized Amber Force Field (GAFF), the AMBER force field for proteins, the accompanying TIP3P water model and the sodium model of Joung and Cheatham. The parameters were developed primarily relying on experimental information -hydration free energies and solution activity derivatives at 0.5 m concentration -with ab initio, gas phase calculations being used for the cases where experimental information is missing. The ab initio parameterization scheme presented here is distinct from other approaches because it explicitly connects gas phase binding energies to intermolecular interactions in solution. We demonstrate that the original GAFF/AMBER parameters often overestimate anion-cation interactions, leading to an excessive number of contact ion pairs in solutions of carboxylate ions, and to aggregation in solutions of divalent ions. GAFF/AMBER parameters lead to excessive numbers of salt bridges in proteins and of contact ion pairs between sodium and acidic protein groups, issues that are resolved by using the optimized parameters presented here.

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Section: Introductionmentioning

confidence: 99%

Developing force fields when experimental data is sparse: AMBER/GAFF-compatible parameters for inorganic and alkyl oxoanions

Kashefolgheta

Verde

2017

Phys. Chem. Chem. Phys.

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“…They conclude that MD simulations provide useful information for RNP enzymes, but that there are limitations in sampling and force field accuracy that make these simulations quite challenging. Finally van der Vaart [21] gives an overview of recent atomistic simulations of the conformational dynamics of protein-DNA complexes, with a focus on DNA deformations that may aid in defining specific binding sites.…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 99%

Editorial preface

Nilsson

Åqvist

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…While molecular dynamics has been used frequently to study protein--DNA--interactions (see for example ref. 3 and references therein), the conventional approach is to start simulations in the DNA bound state. Our simulations, which started in an unbound configuration, reproduced the experimental ERG ETS domain DNA--crystal structure and experimental data for the DNA binding process of ERG with remarkable detail.…”

Section: Discussionmentioning

confidence: 99%

“…Please do not adjust margins ERGp55) on the same helix has been suggested to interact with the 3 A base. 4,16,18 An additional indirect recognition mechanism, by which water molecules acting as bridges for hydrogen bonds between amino acids and DNA bases confer additional sequence specificity outside the GGAA cognate sequence has recently been proposed for other ETS factors.…”

Section: Introductionmentioning

confidence: 99%

“…More recently molecular dynamics techniques have proved invaluable in obtaining dynamic information at the atomic level to interpret experimental results in the field of protein DNA--interactions (see ref. 3 and references therein). In this report we study the DNA--interaction of the transcription factor encoded by the ETS--related Gene (ERG), a member of the E26 transformation specific (ETS) protein family.…”

Section: Introductionmentioning

confidence: 99%

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Molecular dynamics studies on the DNA-binding process of ERG

et al. 2016

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The ETS family of transcription factors regulate gene targets by binding to a core GGAA DNA--sequence. The ETS factor ERG is required for homeostasis and lineage--specific functions in endothelial cells, some subset of haemopoietic cells and chondrocytes; its ectopic expression is linked to oncogenesis in multiple tissues. To date details of the DNA--binding process of ERG including DNA--sequence recognition outside the core GGAA--sequence are largely unknown. We combined available structural and experimental data to perform molecular dynamics simulations to study the DNA--binding process of ERG. In particular we were able to reproduce the ERG DNA--complex with a DNA--binding simulation starting in an unbound configuration with a final root--mean--square--deviation (RMSD) of 2.1 Å to the core ETS domain DNA--complex crystal structure. This allowed us to elucidate the relevance of amino acids involved in the formation of the ERG DNA--complex and to identify Arg385 as a novel key residue in the DNA--binding process. Moreover we were able to show that water--mediated hydrogen bonds are present between ERG and DNA in our simulations and that those interactions have the potential to achieve sequence recognition outside the GGAA core DNA--sequence. The methodology employed in this study shows the promising capabilities of modern molecular dynamics simulations in the field of protein DNA--interactions.

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Coupled binding–bending–folding: The complex conformational dynamics of protein-DNA binding studied by atomistic molecular dynamics simulations

Cited by 29 publications

References 183 publications

Developing force fields when experimental data is sparse: AMBER/GAFF-compatible parameters for inorganic and alkyl oxoanions

Developing force fields when experimental data is sparse: AMBER/GAFF-compatible parameters for inorganic and alkyl oxoanions

Editorial preface

Molecular dynamics studies on the DNA-binding process of ERG

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