Free energy profiles for two ubiquitous damaging agents: methylation and hydroxylation of guanine in B-DNA.
Phys Chem Chem Phys
; 19(22): 14695-14701, 2017 Jun 07.
Article
de En
| MEDLINE
| ID: mdl-28537602
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]Ë intermediate, we challenge the functional dependence of such simulations recently-proposed functionals, such as M06-2X and LC-BLYP, agree on a â¼4 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Méthylation de l'ADN
/
Forme B de l'ADN
/
Guanine
Type d'étude:
Prognostic_studies
Langue:
En
Journal:
Phys Chem Chem Phys
Sujet du journal:
BIOFISICA
/
QUIMICA
Année:
2017
Type de document:
Article
Pays d'affiliation:
France