Targeted DNA oxidation and trajectory of radical DNA using DFT based QM/MM dynamics

Molecular insight into electronic rearrangements and structural trajectories arising from oxidative damages to DNA backbone is of crucial importance in understanding the effect of ionizing radiation, developing DNA biosensors and designing effective DNA cleaving molecules. Employing a Density Functional Theory based multi-scale Quantum-Mechanical-Molecular-Mechanical (QM/MM) simulation and a suitable partitioning of the Hamiltonian on solvated nucleotide, and single-, and double-stranded DNA, we mimic hydrogen transfer reactions from the backbone by OH radicals and report structural trajectories arising from on-the-fly electronic charge- and spin-density redistribution in these three different structural topologies of DNA. Trajectories reveal that H4′ abstraction can disrupt the deoxyribose moiety through the formation of C4′=O4′ ketone and a π-bond with base at C1′-N9 in a nucleotide versus only partial ketone formation in single- and double-stranded DNA, where the orientation of the base is topologically restrained. However, H5′ abstraction can lead DNA cleavage at 5′ end through the formation of C5′=O5′ ketone and breakage of P-O5′ bond. Results demonstrate that structural damages from oxidative reactions are restrained by base stacking and base-pair hydrogen bonding. The methodology can be suitably used to study targeted DNA and RNA damages from radicals and radiomimetic drugs to design DNA cleaving molecules for chemotherapy.