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

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, E. & Pomès, R. Nucleic Acids Research, 39(2):767-780, Oxford University Press, 2011.

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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 [link]

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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 uracilDNAglycosylases (UDG). Recent studies suggest that recognition of UA and UG 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 UA base pairs relative to their natural TA 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 TA and UA pairs lifetimes in the nanosecond timescale. Additionally, we observed spontaneous base flipping in UA 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 UA 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.

@article{
 title = {On the molecular basis of uracil recognition in DNA: comparative study of T-A versus U-A structure, dynamics and open base pair kinetics},
 type = {article},
 year = {2011},
 pages = {767-780},
 volume = {39},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/20876689},
 publisher = {Oxford University Press},
 institution = {School of Chemistry, National University of Ireland, Galway (NUIG), Galway, Ireland. elisa.fadda@nuigalway.ie},
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 abstract = {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 uracilDNAglycosylases (UDG). Recent studies suggest that recognition of UA and UG 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 UA base pairs relative to their natural TA 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 TA and UA pairs lifetimes in the nanosecond timescale. Additionally, we observed spontaneous base flipping in UA 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 UA 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.},
 bibtype = {article},
 author = {Fadda, Elisa and Pomès, Régis},
 journal = {Nucleic Acids Research},
 number = {2}
}

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