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

TL;DR

This study uses multiscale QM/MM simulations to investigate how water influences hydroxyl radical damage to guanine in DNA, revealing water's role in altering reaction pathways and efficiency.

Contribution

First application of multiscale QM/MM to study hydroxyl radical interaction with DNA components in aqueous solution, highlighting water's impact on reaction mechanisms.

Findings

Water alters hydrogen-abstraction pathways by restricting OH radical orientation.

Hydrogen abstraction efficiency is lower in water than in vacuum.

Method enables extension to larger DNA systems without high computational cost.

Abstract

Understanding the damage of DNA bases from hydrogen abstraction by free OH radicals is of particular importance to reveal the effect of hydroxyl radicals produced by the secondary effect of 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 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.