DNA intrastrand cross-links induced by the purine-type deoxyguanosine-8-yl radical: a DFT study

Abstract

Currently, all known DNA intrastrand cross-links are found to be induced by pyrimidine-type radicals; however, whether or not purine-type radicals are able to cause DNA intrastrand cross-links remains unclear. In the present study, probable additions of the highly reactive deoxyguanosine-8-yl radical to its 3′/5′ neighboring pyrimidine nucleotides in four model compounds, 5′-G˙T-3′, 5′-TG˙-3′, 5′-G˙C-3′, and 5′-CG˙-3′, were studied using density functional theory (DFT) methods. In single-stranded DNA, the deoxyguanosine-8-yl radical is preferred to efficiently attack the C5 site of its 3′ neighboring deoxythymidine or deoxycytidine, forming the G[8-5]T or G[8-5]C intrastrand cross-link rather than the C6 site forming the G[8-6]T or G[8-6]C intrastrand cross-link. The four corresponding sequence isomers, namely T[5-8]G, T[6-8]G, C[5-8]G, and C[6-8]G, formed by additions of deoxyguanosine-8-yl radical to its 5′ neighboring pyrimidine nucleotides are predicted to be formed inefficiently. In double-stranded DNA, considering the detrimental effects of stabilizing weak interactions on related structural adjustments required in each addition reaction path, relatively lower reaction yields are suggested for the G[8-5]T and G[8-5]C intrastrand cross-links, while the formation of the other six intrastrand cross-links becomes quite difficult. All calculations definitely demonstrate that, in addition to pyrimidine-type radicals, the purine-type deoxyguanosine-8-yl radical is able to attack its 3′/5′ neighboring pyrimidine nucleotides forming several DNA intrastrand cross-links.