Free energy profiles for two ubiquitous damaging agents: methylation and hydroxylation of guanine in B-DNA. Issue 22 (24th May 2017)

• Record Type: Journal Article
• Authors: Grüber, R.; Aranda, J.; Bellili, A.; Tuñón, I.; Dumont, E.
• Is Part Of: Physical chemistry chemical physics. Volume 19:Issue 22(2017)
• Page Start: 14695
• Page End: 14701
• Publication Date: 2017-05-24
• Subjects: Chemistry, Physical and theoretical -- Periodicals; 541.3
• DOI: 10.1039/c6cp07966k
• Languages: English
• ISSNs: 1463-9076

Abstract

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. 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.