Modeling the dynamics of DNA (photo)lesions: from reactivity to repair

Résumé :

Formation and repair of DNA lesions embrace a rich and combinatorial chemistry, where atomic-scale simulations are increasingly helpful to complement and extent experimental evidences.

The modeling of DNA structure, dynamics, and (photo)chemistry has benefited from a series of recent methodological developments that now allow, for instance capturing DNA-photosensitizers interactions, probing new excited-state mechanisms for DNA lesions induction or photostability [1], and rationalize the photochemistry or photocatalytic properties of drugs within DNA owing to hybrid QM/MM-MD schemes.

I will present a series of examples where computational approaches can palliate, at least partly, the absence of NMR, FRET or X-ray data for damaged DNA oligonucleotides, DNA-drug
binding modes or even DNA-proteins interactions at the nucleosomal scale [2,3]. I will also situate DNA-ligand interactions, which can be helpful for the design of next-generation G-
quadruplex-specific photosensitizers [4] or new DNA-inspired photocatalysts [5].

[1] A. Frances-Monerris, H. Gattuso, D. Roca-Sanjuan, I. Tunon, M. Marazzi, E. Dumont, A. Monari, Chem. Sci., 2018, 9:7902-7911
[2] E. Matouskova, E. Bignon, V. E. P. Claerbout, T. Drsata, N. Gillet, A. Monari. E. Dumont, F. Lankas, J. Chem. Theory. Comput., 2020, 16(9):5972-5981
[3] T. Wen, M. Kermarrec, E. Dumont, N. Gillet, M. M. Greenberg, J. Am. Chem. Soc., 2023, 145(43):23702-23714
[4] M. Deiana et al., Nucl. Acids. Res., 2023, 51(12):6264-6285
[5] Z. Pastorel, J. Zani, M. Noël, A. Bartocci, S. Arseniyadis, E. Dumont, Y. Canac, O. Baslé, M. Smietana, Nat. Comm., 2026, 17:7527

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Contact : anne.milet@univ-grenoble-alpes.fr