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.

Singlet Oxygen Oxidation of the Radical Cations of 8‐Oxo‐2′‐deoxyguanosine and Its 9‐Methyl Analogue: Dynamics, Potential Energy Surface, and Products Mediated by C5‐O2‐Addition

“…The same trend occurs in the adiabatic ionization energies (AIE) of nucleobases, i. e ., AIE=6.38 eV for 8‐oxoguanine, [16] 7.75 eV for guanine, [17] 8.27 eV for adenine, 8.66 eV for cytosine, and 8.82 eV for thymine [18] . Hence, OG acts as a deep trap for charge by forming OG .+ radical cation upon ionizing radiation and one‐electron oxidation, [11e,19] and the OG‐containing DNA becomes more easily oxidizable [20] . A biologically significant scenario is ionizing radiation and 1 O 2 interacting simultaneously with nucleic acids, wherein synergetic damage is anticipated from the combination of OG formation, conversion to OG .+ and reaction with 1 O 2 .…”

Theoretical Modeling of Redox Potentials of Biomolecules

“…Therefore, it is not unexpected that only a few works report a confidence interval of the computed reported potential. However, using the available values reported in the literature [ 16 , 55 , 63 , 64 , 65 , 66 , 67 ], it is likely to assume that a plausible inaccuracy interval is between 5 and 20 kJ/mol.…”

A Force Field for a Manganese-Vanadium Water Oxidation Catalyst: Redox Potentials in Solution as Showcase

“…The approach adopted in the present work for calculating ∆G R→O is based on the methodology first proposed by Warshel [26,27] and applied to one-electron half-reactions of complex systems in the last few years (e.g., see Refs. [28][29][30]). The starting point is the following equation:…”

“…∆E R→O R and ∆E R→O O are the average IE and the average EA, respectively. Within the linear response regime, the reorganization energy λ from Marcus theory can also be computed from the average IE and EA [28][29][30]:…”

“…If the three estimates for the reorganization energy (λ, λ R , λ O ) do not agree, this indicates a deviation from the Marcus regime. Using the "Q-model" developed by Matyushov and Voth [35,36], one can compute an error estimate for the free energy [30]:…”