Computational Prediction of One-Electron Reduction Potentials and Acid Dissociation Constants for Guanine Oxidation Intermediates and Products

Reduction potentials and pKa values
were calculated for intermediates and products along three major pathways
for guanine oxidation using the B3LYP and CBS-QB3 levels of theory
with the SMD implicit solvation model. N-methylated
nucleobases were used as models for nucleoside species. Ensemble averaged
reduction potentials at pH 7 (E7) were
obtained by combining calculated standard reduction potentials with
calculated pKa values in addition to accounting
for tautomerization energies. Calculated pKa values are reasonable based on experimental estimates and chemical
intuition. Pathway A leads to guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp).
The first step is the oxidation of 8-oxoguanine which proceeds by
the loss of an electron followed by the loss of two protons and loss
of another electron, yielding 8-oxopurine. The calculated E7 values for the remaining intermediates and
products are at least 0.3 V higher than that of guanine, indicating
that further oxidation of these species is unlikely. Pathway B leads
to two formamidopyrimidine isomers (FAPyG and 2,5FAPyG). Species along
this pathway have calculated reduction potentials that are much lower
than the oxidation potential for guanine and would likely be very
short-lived in an oxidatively stressed environment. Pathway C leads
to reduced spiroiminodihydantoin and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih).
Similar to pathway A, the calculated reduction potentials for species
along this pathway are at least 0.4 V higher than that of guanine.