Abstract
We modelled the driving force for aqueous keto-to-enol tautomerisation of 5-bromouracil, a mutagenic thymine analogue, by first-principles molecular dynamics simulations with thermodynamic integration. Using interatomic distance constraints to model the water-assisted (de)protonation of 5-bromouracil in a periodic water box, we show that the free energy for its enolisation is lower than that of the parent compound, uracil, by around 3.0 kcal/mol (BLYP-D2 level), enough to significantly alter the relative tautomeric ratios. Assuming the energetic difference also holds in the cell, this finding is evidence for the “rare tautomer” hypothesis of 5-bromouracil mutagenicity (and, possibly, that of other base analogues).
Original language | English |
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Title of host publication | Quantum Systems in Physics, Chemistry and Biology - Theory, Interpretation, and Results |
Editors | Samantha Jenkins, Steven Kirk, Jean Maruani, Erkki Brandas |
Publisher | Academic Press/Elsevier |
Chapter | 5 |
Pages | 109-128 |
ISBN (Print) | 9780128160848 |
DOIs | |
Publication status | Published - 1 Jan 2019 |
Publication series
Name | Advances of Quantum Chemistry |
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Publisher | Academic Press |
Volume | 78 |
ISSN (Print) | 0065-3276 |
Keywords
- Density functional theory
- Nucleobases
- Solvation effects
- Mutagenesis
- CPMD
- Bromouracil
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Thermodynamics of 5-bromouracil tautomerisation from first-principles molecular dynamics simulations (dataset)
Holroyd, L. F. (Creator), Buehl, M. (Creator), Gaigeot, M.-P. (Creator) & Van Mourik, T. (Creator), University of St Andrews, 14 Jan 2019
DOI: 10.17630/4263c8ac-d8fe-48f4-94ef-09abbc302b8b
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