Oxidative Damage to DNA:  Counterion-Assisted Addition of Water to Ionized DNA

Abstract

Oxidative damage to DNA, implicated in mutagenesis, aging, and cancer, follows electron loss that generates a radical cation that migrates to a guanine, where it may react with water to form 8-oxo-7,8-dihydroguanine (8-OxoG). Molecular dynamics and ab initio quantum simulations on a B-DNA tetradecamer reveal activated reaction pathways that depend on the local counterion arrangement. The lowest activation barrier, 0.73 eV, is found for a reaction that starts from a configuration where a Na(+) resides in the major groove near the N7 atoms of adjacent guanines, and evolves through a transition state where a bond between a water oxygen atom and a carbon atom forms concurrently with displacement of a proton toward a neighboring water molecule. Subsequently, a bonded complex of a hydronium ion and the nearest backbone phosphate group forms. This counterion-assisted proton shuttle mechanism is supported by experiments exploiting selective substitution of backbone phosphates by methylphosphonates.

Solvent Effects on Charge Spatial Extent in DNA and Implications for Transfer

“…6). Very recently, the reorientation of water molecules around guanine was also seen to localize the charge on that base [36,38].…”

Electrical Conductance in Biological Molecules

“…For the present, the most frequently used quantummechanical approaches in such studies comprise either tight-binding Hamiltonians (with all their merits and demerits discussed above) and DFT (density functional theory) (see, for example, [54,62,[104][105][106][107][108] and the references therein). Employing the latter also produces many serious problems, like restrictions on the molecular dimensions of model DNA duplexes (still, as mentioned above, the O(n)-linear-scaling DFT approximations might help in partially resolving this poser [105] ), as well as the role of atomic basis set quality.…”

UV Spectra and Excitation Delocalization in DNA: Influence of the Spectral Width

“…This contrasts with the sophisticated calculations, which combine quantum chemistry and molecular dynamics, that have been developed recently to describe charge transfer in DNA. [8][9][10] In the framework of exciton theory, [11][12] the excited states of a multichromophoric system are linear combinations of the excited states of each monomeric chromophore. Their properties are obtained by diagonalization of the Hamiltonian matrix, in which the diagonal and off-diagonal terms represent the excitation energy of the monomer transitions within the examined system and the electronic coupling, respectively.…”