Dinucleotides as simple models of the base stacking-unstacking component of DNA 'breathing' mechanisms

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dc.contributor.authorBeyerle, Eric R.
dc.contributor.authorDinpajooh, Mohammadhasan
dc.contributor.authorJi, Huiying
dc.contributor.authorvon Hippel, Peter H.
dc.contributor.authorMarcus, Andrew H.
dc.contributor.authorGuenza, Marina G.
dc.date.accessioned2022-10-11T00:50:21Z
dc.date.available2022-10-11T00:50:21Z
dc.date.issued2021-01
dc.description14 pagesen_US
dc.description.abstractRegulatory protein access to the DNA duplex 'interior' depends on local DNA 'breathing' fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with the experimental spectra. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson-Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations.en_US
dc.description.sponsorshipThis research was supported by a grant from the National Institute of Child Health and Human Development (5R01HD081 362-05) awarded to L.S. and N.B.A. The funding sources had no role in the study design, data collection and analysis, or submission process.en_US
dc.identifier.citationBeyerle ER, Dinpajooh M, Ji H, von Hippel PH, Marcus AH, Guenza MG. Dinucleotides as simple models of the base stacking-unstacking component of DNA 'breathing' mechanisms. Nucleic Acids Res. 2021 Feb 26;49(4):1872-1885. doi: 10.1093/nar/gkab015. PMID: 33503257; PMCID: PMC7913701.en_US
dc.identifier.urihttps://hdl.handle.net/1794/27672
dc.identifier.urihttps://doi.org/10.1093/nar/gkab015en_US
dc.language.isoenen_US
dc.publisherOxford Academicen_US
dc.rightsCreative Commons BY-NC-ND 4.0-USen_US
dc.subjectCircular Dichroismen_US
dc.subjectDNAen_US
dc.subjectMarkov Chainsen_US
dc.subjectMolecular Modelsen_US
dc.subjectSodium Chlorideen_US
dc.titleDinucleotides as simple models of the base stacking-unstacking component of DNA 'breathing' mechanismsen_US
dc.typeArticleen_US

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