Despite its stability, DNA is sensitive to stress (UV light, reactive oxygen species…) which can damage the different nucleobases in the genetic code. We use classical and hybrid
quantum/classical (QM/MM) molecular dynamic simulations (MDs) to bring a molecular insight to the relationship between DNA conformations and the formation of such damages.
We have considered three main challenges: i) characterize the transfer and the reactivity of the triplet state of thymine (3T) in free DNA; ii) understand the impact of the nucleosome structure on cyclobutane dimer (CPD) formation; iii) improve the binding of small molecules by oxidized aptamers.
3T can be considered as a precursor of CPD formation. Applying QM/MM-MDs approaches, we simulated its energy transfer along a TTTT sequence embedded in B-DNA strands. We observe a highly localized but mobile triplet state and demonstrate a likely correlation between its energy and DNAdynamics.We then focus on the CPD formation from the 3T state using an umbrella sampling approach at DFT/MM level for Both TpT and CpT adducts. Our simulations underline the dramatic impact of the starting conformation of the reaction energies.
We then want to study the nucleosome, which consists of 147 DNAbase pairs wrapped around an octameric histone core. Starting from a large conformational sampling of the flexible histone tails, obtained by replica exchange approach, and a crystallographic structure of the nucleosome core, we run microsecond timescale MDs. Eventually, we can analyze the geometrical parameters of the TpT and CpT dimers with regards to the CPD formation.
In the last part, we focus on the interaction between a nucleic acid aptamer and its target, including different 8-oxopurines as ligand or in the receptor. MDs helped us to characterize the targets binding sites and analyze the effect of the different oxidations to compare with the experimental affinity.