QM/MM investigations of DNA lesions: what can we learn so far ?
Résumé
Whereas DNA is conceptually simpler than proteins, as a polymer with 4 constitutive nucleobases vs. 20 residues, it presents a rich oxidatively-induced and photoinduced chemistry that gives rise to potentially more than 70 lesions identified by spectrometry HPLC-MS/MS. Some intermediates are known to be central in the oxidation cascade, such as the radical cation of guanine, but the mechanisms leading to DNA lesions are poorly identified. Analogously, the triplet state of thymine is the hotspot for photolesions, and generated widely through photosensitization (2). I will present our recent and ongoing QM/MM efforts to investigate the mechanistic pathways for important lesions (1), stressing the need for new efficient computational schemes. I will also exemplify the combinatorial nature of DNA lesions induction that calls for efficient hybrid schemes, with the need to describe the dynamic nature of DNA lesions.
References
(1) Dumont E., Gruber R., Bignon E., Morell C., Aranda J., Ravanat J.-L., Tunon I. Chem. Eur. J., 2016, 22 (32), 12358-12362
(2) Epe, B. Photochem. Photobiol. Sci., 2012, 11, 98-106.
This work was performed within the framework of the LABEX PRIMES (ANR-11-LABX-0063) of Université de Lyon.