Probing the mechanistic pathways and structural aftermaths of complex DNA lesions
Résumé
The structural elucidation of complex lesions is extremely challenging and many questions unanswered and modelling insights are sought to corroborate multistep mechanisms that are currently only postulated, even for the prototypical 8-oxoguanine.
Static calculations, most often based on a DFT framework, have proved their relevance yet beyond single-nucleotide lesions we will show that they can be associated to a spurious description due to the formation of hydrogen bonds between dinucleosides and a deviation from an acceptable and representative pi-stacked structure. We lift these limitations resorting to hybrid QM/MM-MD simulations [1]: the B-DNA environment is realistically taken into account and we prove in passing that the B-helix embedding can reverse the intrinsic electronic reactivity of hydrogen-abstracted pyrimidines [2].
We also rely on classical MD simulations to generate representatives structures of oligonucleotides featuring one or several lesions. This enables to monitor the B-helix distortion and the outcome of the initial Watson-Crick pairing: this way, we shed light on the lack of repair of tandem lesions [3].