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    On the molecular basis of uracil recognition in DNA: comparative study of T-A versus U-A structure, dynamics and open base pair kinetics

    Fadda, Elisa and Pomès, Régis (2011) On the molecular basis of uracil recognition in DNA: comparative study of T-A versus U-A structure, dynamics and open base pair kinetics. Nucleic Acids Research, 39 (2). pp. 767-780. ISSN 0305-1048

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    Uracil (U) can be found in DNA as a mismatch paired either to adenine (A) or to guanine (G). Removal of U from DNA is performed by a class of enzymes known as uracil–DNA–glycosylases (UDG). Recent studies suggest that recognition of U–A and U–G mismatches by UDG takes place via an extra-helical mechanism. In this work, we use molecular dynamics simulations to analyze the structure, dynamics and open base pair kinetics of U–A base pairs relative to their natural T–A counterpart in 12 dodecamers. Our results show that the presence of U does not alter the local conformation of B-DNA. Breathing dynamics and base pair closing kinetics are only weakly dependent on the presence of U versus T, with open T–A and U–A pairs lifetimes in the nanosecond timescale. Additionally, we observed spontaneous base flipping in U–A pairs. We analyze the structure and dynamics for this event and compare the results to available crystallographic data of open base pair conformations. Our results are in agreement with both structural and kinetic data derived from NMR imino proton exchange measurements, providing the first detailed description at the molecular level of elusive events such as spontaneous base pair opening and flipping in mismatched U–A sequences in DNA. Based on these results, we propose that base pair flipping can occur spontaneously at room temperature via a 3-step mechanism with an open base pair intermediate. Implications for the molecular basis of U recognition by UDG are discussed.

    Item Type: Article
    Keywords: base pairing; dna; molecular conformation; uracil; kinetics;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 7826
    Identification Number:
    Depositing User: Elisa Fadda
    Date Deposited: 30 Jan 2017 15:09
    Journal or Publication Title: Nucleic Acids Research
    Publisher: Oxford University Press
    Refereed: Yes
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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