Ab initio molecular orbital calculations of stacked DNA bases were performed at the 3-21G(*) and 6-31G* levels to elucidate the origin of the 5‘-GG-3‘ sequence specificity for the photocleavage of DNA in the presence of electron-accepting photosensitizers. Ionization potentials (IP) were estimated as Koopman's theorem values for 16 sets of two stacked nucleobases and seven sets of stacked nucleobase pair systems in a B-form geometry. It was found that the GG/CC system is the lowest among the 10 possible stacked nucleobase pairs and that approximately 70% of the HOMO is localized on the 5‘-G of 5‘-GG-3‘. These calculations indicate that the 5‘-G of 5‘-GG-3‘ is the most electron donating site in B DNA and suggest that one-electron transfer from DNA to an electron acceptor occurs most effectively at 5‘-GG-3‘ sites which are fully consistent with the experimental data. In order to know the fate of the cation radical, the vertical IPs were estimated for seven stacked nucleobase pairs. It was found that the GG/CC system possesses the smallest vertical IP and that the cation radical is localized on the 5‘-G of 5‘-GG-3‘. These results imply that the 5‘-G of 5‘-GG-3‘ is a sink in “hole” migration through DNA, i.e., an electron-loss center created in a B-form DNA will end up predominantly on the 5‘-G of 5‘-GG-3‘, and suggest that not only the base specificity for initial photoionization but also subsequent energetically favored hole migration to the lowest 5‘-GG-3‘ site are the origin of the 5‘-GG-3‘ specific cleavage. Calculations of stacked GGs with various geometries including orientations of A- and Z-form DNA were also examined.

There has been much current interest in the long-range oxidative damage to DNA through the DNA duplex caused by one-electron oxidations. 1 Hole (radical cation) migration through the DNA duplex has been suggested to play a crucial role in mutagenesis and carcinogenesis caused by carcinogenic agents, ionizing radiation, and high-intensity laser irradiation. 1,2 As is well-known, guanine (G) is the most easily oxidized base, 3 and the electron-loss center created in duplex DNA ultimately ends up at G residues via hole migration through the DNA duplex. Several years ago, we demonstrated both experimentally and by ab initio calculations that 5′-G residues of 5′-GG-3′ steps in B-form DNA are the most easily oxidized due to the GG stacks and can act as thermodynamic sinks in hole migration across the DNA π stack. 4 We also demonstrated that the highest occupied molecular orbital (HOMO) of a GG stack is especially high in energy and concentrated on the 5′-G. 4b Thereafter, examples of 5′-G selective oxidations have been reported in many different systems. These include (i) photooxidation using different types of DNA-binding agents such as Rh(III)-metallointercalators, 1a-c,f substituted anthraquinones, 1d,e,5 riboflavin, 6 naphthalimide derivatives, 4 a p-cyano-substituted benzophenone, 7 and pterins; 8 (ii) chemical oxidation by Ru(III)-metallointercalators 1c,9 and Ni(II)ligand/sulfite system; 10 (iii) two-photon photoionization of DNA with a high-intensity laser pulse (266 nm); 11 and (iv) direct irradiation with a powerful 193-nm excimer laser. 12 Notably, the 5′-G selectivity of 5′-GG-3′ steps is irrelevant to the structural

while the complementary strand 3 was unchanged (Scheme 1).