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Theoretical modelling of epigenetically modified DNA sequences

We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result...

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Autores principales: Carvalho, Alexandra Teresa Pires, Gouveia, Maria Leonor, Raju Kanna, Charan, Wärmländer, Sebastian K. T. S., Platts, Jamie, Kamerlin, Shina Caroline Lynn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: F1000Research 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582758/
https://www.ncbi.nlm.nih.gov/pubmed/26448859
http://dx.doi.org/10.12688/f1000research.6148.2
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author Carvalho, Alexandra Teresa Pires
Gouveia, Maria Leonor
Raju Kanna, Charan
Wärmländer, Sebastian K. T. S.
Platts, Jamie
Kamerlin, Shina Caroline Lynn
author_facet Carvalho, Alexandra Teresa Pires
Gouveia, Maria Leonor
Raju Kanna, Charan
Wärmländer, Sebastian K. T. S.
Platts, Jamie
Kamerlin, Shina Caroline Lynn
author_sort Carvalho, Alexandra Teresa Pires
collection PubMed
description We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result in rather larger changes to hydrogen-bond and stacking binding energies, as predicted by dispersion-corrected density functional theory (DFT) methods. The same modifications within double-stranded GCG and ACA trimers exhibit rather larger structural effects, when including the sugar-phosphate backbone as well as sodium counterions and implicit aqueous solvation. In particular, changes are observed in the buckle and propeller angles within base pairs and the slide and roll values of base pair steps, but these leave the overall helical shape of DNA essentially intact. The structures so obtained are useful as a benchmark of faster methods, including molecular mechanics (MM) and hybrid quantum mechanics/molecular mechanics (QM/MM) methods. We show that previously developed MM parameters satisfactorily reproduce the trimer structures, as do QM/MM calculations which treat bases with dispersion-corrected DFT and the sugar-phosphate backbone with AMBER. The latter are improved by inclusion of all six bases in the QM region, since a truncated model including only the central CG base pair in the QM region is considerably further from the DFT structure. This QM/MM method is then applied to a set of double-stranded DNA heptamers derived from a recent X-ray crystallographic study, whose size puts a DFT study beyond our current computational resources. These data show that still larger structural changes are observed than in base pairs or trimers, leading us to conclude that it is important to model epigenetic modifications within realistic molecular contexts.
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spelling pubmed-45827582015-10-06 Theoretical modelling of epigenetically modified DNA sequences Carvalho, Alexandra Teresa Pires Gouveia, Maria Leonor Raju Kanna, Charan Wärmländer, Sebastian K. T. S. Platts, Jamie Kamerlin, Shina Caroline Lynn F1000Res Research Article We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result in rather larger changes to hydrogen-bond and stacking binding energies, as predicted by dispersion-corrected density functional theory (DFT) methods. The same modifications within double-stranded GCG and ACA trimers exhibit rather larger structural effects, when including the sugar-phosphate backbone as well as sodium counterions and implicit aqueous solvation. In particular, changes are observed in the buckle and propeller angles within base pairs and the slide and roll values of base pair steps, but these leave the overall helical shape of DNA essentially intact. The structures so obtained are useful as a benchmark of faster methods, including molecular mechanics (MM) and hybrid quantum mechanics/molecular mechanics (QM/MM) methods. We show that previously developed MM parameters satisfactorily reproduce the trimer structures, as do QM/MM calculations which treat bases with dispersion-corrected DFT and the sugar-phosphate backbone with AMBER. The latter are improved by inclusion of all six bases in the QM region, since a truncated model including only the central CG base pair in the QM region is considerably further from the DFT structure. This QM/MM method is then applied to a set of double-stranded DNA heptamers derived from a recent X-ray crystallographic study, whose size puts a DFT study beyond our current computational resources. These data show that still larger structural changes are observed than in base pairs or trimers, leading us to conclude that it is important to model epigenetic modifications within realistic molecular contexts. F1000Research 2015-05-06 /pmc/articles/PMC4582758/ /pubmed/26448859 http://dx.doi.org/10.12688/f1000research.6148.2 Text en Copyright: © 2015 Carvalho ATP et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Carvalho, Alexandra Teresa Pires
Gouveia, Maria Leonor
Raju Kanna, Charan
Wärmländer, Sebastian K. T. S.
Platts, Jamie
Kamerlin, Shina Caroline Lynn
Theoretical modelling of epigenetically modified DNA sequences
title Theoretical modelling of epigenetically modified DNA sequences
title_full Theoretical modelling of epigenetically modified DNA sequences
title_fullStr Theoretical modelling of epigenetically modified DNA sequences
title_full_unstemmed Theoretical modelling of epigenetically modified DNA sequences
title_short Theoretical modelling of epigenetically modified DNA sequences
title_sort theoretical modelling of epigenetically modified dna sequences
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582758/
https://www.ncbi.nlm.nih.gov/pubmed/26448859
http://dx.doi.org/10.12688/f1000research.6148.2
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