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Sequence dependency of canonical base pair opening in the DNA double helix
KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
2017 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, no 4, e1005463Article in journal (Refereed) Published
Abstract [en]

The flipping-out of a DNA base from the double helical structure is a key step of many cellular processes, such as DNA replication, modification and repair. Base pair opening is the first step of base flipping and the exact mechanism is still not well understood. We investigate sequence effects on base pair opening using extensive classical molecular dynamics simulations targeting the opening of 11 different canonical base pairs in two DNA sequences. Two popular biomolecular force fields are applied. To enhance sampling and calculate free energies, we bias the simulation along a simple distance coordinate using a newly developed adaptive sampling algorithm. The simulation is guided back and forth along the coordinate, allowing for multiple opening pathways. We compare the calculated free energies with those from an NMR study and check assumptions of the model used for interpreting the NMR data. Our results further show that the neighboring sequence is an important factor for the opening free energy, but also indicates that other sequence effects may play a role. All base pairs are observed to have a propensity for opening toward the major groove. The preferred opening base is cytosine for GC base pairs, while for AT there is sequence dependent competition between the two bases. For AT opening, we identify two non-canonical base pair interactions contributing to a local minimum in the free energy profile. For both AT and CG we observe long-lived interactions with water and with sodium ions at specific sites on the open base pair.

Place, publisher, year, edition, pages
Public Library of Science , 2017. Vol. 13, no 4, e1005463
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-209322DOI: 10.1371/journal.pcbi.1005463ISI: 000402542900019ScopusID: 2-s2.0-85018285834OAI: oai:DiVA.org:kth-209322DiVA: diva2:1111441
Funder
EU, European Research Council, 258980Swedish Research Council, 2015-04992Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170619

Available from: 2017-06-19 Created: 2017-06-19 Last updated: 2017-06-19Bibliographically approved

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CiteExportLink to record
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Citation style
  • apa
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