Mapping of highest occupied molecular orbitals of duplex DNA by cobalt-mediated guanine oxidation

We have examined the oxidation of oligodeoxynucleotides (ODN) containing va rious guanine (G)containing sequences with Co(II) ion and benzoyl peroxide (BPO). Sequence-dependent G-cleavage has been observed for double-stranded ODN as revealed by PAGE analysis of the reaction mixture after hot piperidi ne treatment, whereas non-selective equal G cleavage was observed for singl e-stranded ODN. The relative rates of sequence-dependent G oxidation were d etermined by densitometric assay of the DNA cleavage bands. We then perform ed ab initio calculations of HOMOs of the G-containing sequences with B-for m geometry at the HF/6-31G* level. Experimentally observed relative rates o f G oxidation matched well with the calculated HOMOs of the G-containing se quences. Thus, the DNA cleavage data obtained from the oxidation of duplex ODNs with Co(II) ion in the presence of BPO correlated nicely with calculat ed HOMOs, implying that the co(II) ion is coordinated more strongly to the G having a larger HOMO. These results suggest that the coordination of Co(I I) ion to the N-7 Of guanine base in a duplex DNA is a HOMO-controlled proc ess, in accordance with the previous NMR studies: on the sequence-dependent binding of Co(II) ion to the N-7 Of guanine base of duplex ODN. After perf orming ab initio calculations of a number of G-containing sequences, we fou nd important general trends that represent the distribution of HOMOs of G b ases in B-form DNA. The results of HOMO mapping described here are extremel y important for predicting: (i) which G-sites are more susceptible to elect rophilic attack in chemical and biological reactions, such as DNA alkylatio n by antitumor drugs or mutagens, and (ii) which G-sites are more prone to HOMO-LUMO interactions with DNA-binding drugs and proteins. These results p rovide a new tool for probing the heterogeneity of DNA sequences.