Solvent Effects on Ionization Potentials of Guanine Runs and Chemically Modified Guanine in Duplex DNA: Effect of Electrostatic Interaction and Its Reduction due to Solvent

Abstract

We examined the ionization potential (IP) corresponding to the free energy of a hole on duplex DNA by semiempirical molecular orbital theory with a continuum solvent model. As for the contiguous guanines (a guanine run), we found that the IP in the gas phase significantly decreases with the increasing number of nucleotide pairs of the guanine run, whereas the IP in water (OP, oxidation potential) only slightly does. The latter result is consistent with the experimental result for DNA oligomers in water. This decrease in the IP is mainly due to the attractive electrostatic interaction between the hole and a nucleotide pair in the duplex DNA. This interaction is reduced in water, which results in the small decrease in the IP in water. This mechanism explains the discrepancy between the experimental result and the previous computational results obtained by neglecting the solvent. As for the chemically modified guanine, the previous work showed that the removal of some solvent (water) molecules due to the attachment of a neutral functional group to a guanine in a duplex DNA stabilizes the hole on the guanine. One might naively have expected the opposite case, since a polar solvent usually stabilizes ions. This mechanism also explains this unexpected stabilization of a hole as follows. When some water molecules are removed, the attractive electrostatic interaction stabilizing the hole increases, and thus, the hole is stabilized. In order to design the hole energetics by a chemical modification of DNA, this mechanism has to be taken into account and can be used.

Solvent Exposure Associated with Single Abasic Sites Alters the Base Sequence Dependence of Oxidation of Guanine in DNA in GG Sequence Contexts

“…The enhancement of oxidatively generated guanine damage increases with the number of contiguous guanines according to 5′‐G<5′‐GG<5′‐GGG, and this phenomenon is correlated with the calculated guanine ionization potentials (IP) in the gas phase,5, 9 as well as in the hydrated state in duplex DNA 10. 11 The “holes” (guanine radical cations) are delocalized with different probabilities among the different guanines in GG and GGG sequences, as shown theoretically12–14 and experimentally 9. 15, 16 The 5′‐G is more easily oxidized and yields greater proportions of hot‐alkali‐labile end‐products than the 3′‐G in 5′⋅⋅⋅GG⋅⋅⋅ sequence contexts, while single guanines flanked by bases other than G in double‐stranded DNA are much less reactive (e.g., refs.…”

“…1) Accessibility of guanines in DNA to solvent‐borne oxidants: abasic sites partially destabilize the local environment,25 and thus increase the exposure of nucleobases to solvent (e.g., ref. 32); and 2) enhanced hydration of guanines is known to lower the reduction potentials of guanine radicals,10, 11, 17, 41–43 and this can occur to different extents in guanines flanked by or opposite an abasic site. While the first factor is expected to enhance the overall levels of guanine oxidation, the second governs the localization of the hole at one of the two guanines, and thus the distribution of oxidatively generated damage at the different guanines.…”

Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes

“…We interpret these composite observations as follows. The IP values for G-runs have been shown to decrease asymptotically with tract length, although the absolute values vary according to the methods and assumptions used (we obtained a value of 5.43 eV for both G[6] and G[9]) ( 64 , 65 ). We suggest that short G-runs with high IPs undergo one-electron oxidation reactions in the oxidative environment of cancer cells but would be refractory to such a mechanism in the germline (Figure 7F right yellow and left white sectors).…”

Sequence and conformation effects on ionization potential and charge distribution of homo-nucleobase stacks using M06-2X hybrid density functional theory calculations

“…Pentameric Ade stacks in B-conformation have also been studied by mixed MD and density functional theory (DFT) calculations ( Improta, 2008 ) and showed that the HOMO of the cationic species is delocalized over the three central adenines. The ionization potential of B-form Gua = Cyt duplexes consisting of up to 6 nucleotide pairs was evaluated in gas phase and water using semi-empirical AM1 calculations ( Yokojima, Yoshiki, Yanoi, & Okada, 2009 ). It was shown to decrease with increasing duplex length in gas phase, but this decrease is reduced in water.…”