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Issue 22, 2017
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Free energy profiles for two ubiquitous damaging agents: methylation and hydroxylation of guanine in B-DNA

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Abstract

DNA methylation and hydroxylation are two ubiquitous reactions in DNA damage induction, yet insights are scarce concerning the free energy of activation within B-DNA. We resort to multiscale simulations to investigate the attack of a hydroxyl radical and of the primary diazonium onto a guanine embedded in a solvated dodecamer. Reaction free energy profiles characterize two strongly exergonic processes, yet allow unprecedented quantification of the barrier towards this damage reaction, not higher than 6 kcal mol−1 and sometimes inexistent, and of the exergonicities. In the case of the [G(C8)-OH]˙ intermediate, we challenge the functional dependence of such simulations: recently-proposed functionals, such as M06-2X and LC-BLYP, agree on a ∼4 kcal mol−1 barrier, whereas the hybrid GGA B3LYP functional predicts a barrier-less pathway. In the long term, multiscale approaches can help build up a unified panorama of DNA lesion induction. These results stress the importance of DFT/MM-MD simulations involving new functionals towards the sound modelling of biomolecule damage even in the ground state.

Graphical abstract: Free energy profiles for two ubiquitous damaging agents: methylation and hydroxylation of guanine in B-DNA

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Publication details

The article was received on 21 Nov 2016, accepted on 21 Apr 2017 and first published on 26 Apr 2017


Article type: Paper
DOI: 10.1039/C6CP07966K
Citation: Phys. Chem. Chem. Phys., 2017,19, 14695-14701
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    Free energy profiles for two ubiquitous damaging agents: methylation and hydroxylation of guanine in B-DNA

    R. Grüber, J. Aranda, A. Bellili, I. Tuñón and E. Dumont, Phys. Chem. Chem. Phys., 2017, 19, 14695
    DOI: 10.1039/C6CP07966K

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