Thermodynamics of 5-bromouracil tautomerisation from first-principles molecular dynamics simulations
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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).
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 , pp. 109-128 . https://doi.org/10.1016/bs.aiq.2018.05.001
Quantum Systems in Physics, Chemistry and Biology - Theory, Interpretation, and Results
© Academic Press 2019. This work has been made available online with permission. This is the author created accepted version manuscript following peer review and as such may differ slightly from the final published version. The final published version of this work will be available at https://doi.org/10.1016/bs.aiq.2018.05.001
DescriptionThe 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).
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