Oxidative damage to DNA: counterion-assisted addition of water to ionized DNA.
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.
Barnett
Robert N
RN
Schools of Physics and Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
Bongiorno
Angelo
A
Cleveland
Charles L
CL
Joy
Abraham
A
Landman
Uzi
U
Schuster
Gary B
GB
D001483:Base Sequence; D004249:DNA Damage; D006147:Guanine / Q000737:chemistry; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010084:Oxidation-Reduction; D014867:Water / Q000737:chemistry*
D014867:Water; D006147:Guanine