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

Pradip K Biswas,Sandipan Chakraborty

doi:10.1093/nar/gkz089

Abstract

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.

Highlights

Free radicals of cellular or external origin and radiomimetic drugs can cause oxidative damage to cellular DNA and RNA [1,2,3]
For the nucleotide, when we took the phosphate, the deoxyribose, and the OH in the QM subsystem leaving the attached base and the solvent water to be treated by MM, we found that the H4 abstraction does not have the expected effect of the formation of a ketone at C4 -O4 as C1’ is restricted to have any electronic rearrangement with the base since N9 is partitioned into the classical MM system
We show that by employing the hybrid QM/MM molecular dynamics simulation protocol to single- and double-stranded DNA together in explicit water, it is possible to study the molecular mechanism of DNA damage reaction pathways and generate structural trajectories from hydrogen abstraction by an OH radical

Summary

Introduction

Free radicals of cellular or external origin (e.g. radiation induced) and radiomimetic drugs can cause oxidative damage to cellular DNA and RNA [1,2,3]. To understand oxidative damage to DNA and strand scission [1,7,8,9,10,11,12,13] or to develop synthetic molecules for DNA cleavage [3,14,15] or DNA biosensors, it is essential to identify the shortlived intermediaries considering the structural constraints present in a single- or double-stranded DNA in physiologically relevant conditions This presents an enormous challenge for computational chemists and it is difficult to identify the short-lived and chemically similar intermediaries in experimental set-up. We describe a Density Functional Theory (DFT) based multi-scale QuantumMechanical-Molecular-Mechanical (QM/MM) simulation technique to elucidate the structural trajectory of oxidative DNA damage pathways

Methods

Results

Conclusion