Mapping DNA-Photosensitizers Interaction In and Out the Nucleosome
Résumé
Formation and repair of DNA lesions embraces a rich and combinatorial chemistry, where atomic-scale simulations are most helpful to complement and expand experimental evidences. This biopolymer constitutes a critical testcase at the crossroad of several timely methodological developments of GPU-accelerated MD codes, polarizable force fields and multiscale approaches [1].
I will present our recent efforts to achieve a robust, computationally-driven description of photosensitizers interacting with DNA. Intensive molecular dynamics allow to map the hot spots for DNA lesion induction and delineate rule-of-thumbs for the non-covalent forces that drive sequence recognition [2]. This allows to build DNA-photosensitizer structures, palliating the absence of NMR or X-ray data for labile drugs, and investigate triplet-triplet energy transfer [3], probe new excited-state mechanisms for DNA photostability [4] and rationalize the DNA-dependent photochemistry of DNA drugs [4] owing to QM/MM-MD schemes. The computational efficiency of the MD-then/QM/MM schemes allows to tackle to chemistry within the nucleosome that unveil interactions between DNA defects and histone tails.
[1] (a) C. Zhang et al., J Chem Theory Comput., 2018, 14:2084-2108 ; (b) I. Ivani et al., Nat. Methods. 2016, 13:55-58
[2] E. Bignon et al., Chem. Eur. J., 2017, 23:12845-12852
[3] E. Dumont et al., J. Phys. Chem. Lett, 2015, 6:576-580
[4] A. Francés-Monerris et al., Chem. Sci., 2018, 9:7902-7911