Thermodynamics of 5-bromouracil tautomerisation from first-principles molecular dynamics simulations
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).
Citation
Holroyd , L F , Buehl , M , Gaigeot , M-P & van Mourik , T 2019 , Thermodynamics of 5-bromouracil tautomerisation from first-principles molecular dynamics simulations . in S Jenkins , S Kirk , J Maruani & E Brandas (eds) , Quantum Systems in Physics, Chemistry and Biology - Theory, Interpretation, and Results . Advances of Quantum Chemistry , vol. 78 , Academic Press/Elsevier , pp. 109-128 . https://doi.org/10.1016/bs.aiq.2018.05.001
Publication
Quantum Systems in Physics, Chemistry and Biology - Theory, Interpretation, and Results
ISSN
0065-3276Type
Book item
Description
The authors acknowledge support from the Engineering and Physical Sciences Research Council (EPSRC) UK National Service for Computational Chemistry Software (NSCCS); from GENCI (Grand équipement national de calcul intensif); and from CINES (Centre informatique national de l’enseignement supérieur). LFH and TvM gratefully acknowledge support from the HPC-EUROPA2 project with the support of the European Commission - Capacities Area - Research Infrastructures. LFH is grateful to the EPSRC for studentship support through the Doctoral Training Account scheme (grant code EP/K503162/1).Collections
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