Publication

Redox Properties of Native and Damaged DNA from Mixed Quantum Mechanical/Molecular Mechanics Molecular Dynamics Simulations

Abstract

The redox properties of two large DNA fragments composed of 39 base pairs, differing only by an 8-oxoguanine (8oxoG) defect replacing a guanine (G), were investigated in physiological conditions using mixed quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations. The quantum region of the native fragment comprised 3 G-C base pairs, while one G was replaced by an 8oxoG in the defect fragment. The calculated values for the redox free energy are 6.55 +/- 0.28 eV and 5.62 +/- 0.30 eV for the native and the 8oxoG-containing fragment, respectively. The respective estimates for the reorganization free energy are 1.25 +/- 0.18 eV and 1.00 +/- 0.18 eV. Both reactions follow the Marcus theory for electron transfer. The large difference in redox potential between the two fragments shows that replacement of a G by an 8oxoG renders the DNA more easily oxidizable. This finding is in agreement with the suggestion that DNA fragments containing an 8oxoG defect can act as sinks of oxidative damage that protect the rest of the genome from assault. In addition, the difference in redox potential between the native and the defect DNA fragment indicates that a charge transfer-based mechanism for the recognition of DNA defects might be feasible, in line with recent suggestions based on experimental observations.

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Related concepts (32)
Okazaki fragments
Okazaki fragments are short sequences of DNA nucleotides (approximately 150 to 200 base pairs long in eukaryotes) which are synthesized discontinuously and later linked together by the enzyme DNA ligase to create the lagging strand during DNA replication. They were discovered in the 1960s by the Japanese molecular biologists Reiji and Tsuneko Okazaki, along with the help of some of their colleagues. During DNA replication, the double helix is unwound and the complementary strands are separated by the enzyme DNA helicase, creating what is known as the DNA replication fork.
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes.
Redox
Redox (ˈrɛdɒks , ˈriːdɒks , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a decrease in the oxidation state. There are two classes of redox reactions: Electron-transfer – Only one (usually) electron flows from the atom being oxidized to the atom that is reduced. This type of redox reaction is often discussed in terms of redox couples and electrode potentials.
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