Multiscale QM/MM Molecular Dynamics Study on the First Steps of Guanine Damage by Free Hydroxyl Radicals in Solution

Abstract

Understanding the damage of DNA bases from hydrogen abstraction by free OH radicals is of particular importance to understanding the indirect effect of ionizing radiation. Previous studies address the problem with truncated DNA bases as ab-initio quantum simulation required to study such electronic spin dependent processes are computationally expensive. Here, for the first time, we employ a multiscale and hybrid Quantum-Mechanical-Molecular-Mechanical simulation to study the interaction of OH radicals with guanine-deoxyribose-phosphate DNA molecular unit in the presence of water where all the water molecules and the deoxyribose-phosphate fragment are treated with the simplistic classical Molecular-Mechanical scheme. Our result illustrates that the presence of water strongly alters the hydrogen-abstraction reaction as the hydrogen bonding of OH radicals with water restricts the relative orientation of the OH-radicals with respective to the DNA base (here guanine). This results in an angular anisotropy in the chemical pathway and a lower efficiency in the hydrogen abstraction mechanisms than previously anticipated for identical system in vacuum. The method can easily be extended to single and double stranded DNA without any appreciable computational cost as these molecular units can be treated in the classical subsystem as has been demonstrated here.

Reactive Molecular Dynamics Study on the First Steps of DNA Damage by Free Hydroxyl Radicals

“…2 reveals more details on H 2 O 2 formation and their lower reactivity with DNA-molecule. Consistent with our recent QM/MM calculation in the solution 15 , we observe that because of the hydrogen bond network forming between OH-radicals and water molecules the time for hydrogen abstraction is longer compare to similar simulation in vacuum.…”

“…Recently ab-initio simulations of the hydrogen abstraction were developed [11][12][13][14][15] . However realistic modeling of DNA molecule with its environment requires extensive computer resources and is a major draw-back of QM methods.…”

“…However realistic modeling of DNA molecule with its environment requires extensive computer resources and is a major draw-back of QM methods. The DFT calculation for hydrogen abstraction in vacuum is limited to the initial damage of a single base [11][12][13] or single sugar-moiety 15 . Despite recent advances in QM/MM methods that allows simulation of larger molecules 14 and inclusion of solvation 15 , the real time simulation of DNA-damage remains still elusive.…”

“…The oxygen from OH radical weaken the C-N bond that attaches the sugar-moiety with the nucleotide-base. To investigate such possibility and the consistency of ReaxFF with DFT, we employed an ab-initio CPMD calculation in vacuum as well as a QMMM CPMD-GROMACS that allows adding realistic solution 15 . The results are shown in Fig.…”

DFT study on the attacking mechanisms of H and OH radicals to G-C and A-T base pairs in water

“…Classical molecular mechanics (MM) and MD simulations cannot consider the effect of electrons and spins explicitly, so that these classical simulations cannot properly describe the reaction mechanism controlled by radicals. Recently, theoretical studies based on ab initio molecular orbital (MO) calculations were carried out [10][11][12][13][14][15]. However, these studies were performed only on the DNA bases, and there is no MO or density functional theory (DFT) calculation investigating the difference in the reaction mechanism between G-C and A-T base pairs induced by OH and H radicals.…”