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Photoinduced Formation Mechanism of the Thymine-Thymine (6-4) Adduct in DNA; a QM(CASPT2//CASSCF):MM(AMBER) study

Abstract

The UVB-induced photomechanism leading the carbonyl group of a thymine nucleobase to react with the carbon-carbon double bond of consecutive thymine nucleobase in a DNA strand to form the thymine-thymine (6-4) adduct photodamage remains nowadays poorly understood. Key questions remain open, concerning both the intrinsic features of the photoreaction (as the contribution (or not) of triplet states, the nature of the involved states, the time-scale of the photoprocess), and the role play by the non-reactive surrounding of the two reactive pyrimidine nucleobases (as the nature of the flanked nucleobases and the flexibility of the whole DNA molecule). A reduced number of theoretical studies have been conducted on the title photoreaction, most of which have been performed on reduced model systems of DNA, consequently neglecting potential key parameters for the photoreaction as the constrains due to the double strain structure and the presence of pairs and stacked nucleobases. In the present contribution the photoactivated step of the title reaction has been studied in a DNA system, and in particular for a specific DNA hairpin for which the quantum yield of formation of the photodamage has been recently experimentally measured. The reaction has been characterized performing high-level QM/MM computations, combining the CASPT2//CASSCF approach for the study of the reactive part (i.e. the two thymine molecules) with an MM-Amber treatment of the surrounding environment. The possibility of a reaction path along both the singlet and triplet manifolds have been characterized, the nature of the reactive states have been analyzed, and the role played by the flexibility of the whole system, which in turn determines the initial accessible geometrical conformations, has been evaluated, consequently providing a substantial contribution towards the elucidation of the photoreaction mechanism. On the basis of the obtained results, a charge-transfer state can decay from a pro-reactive initial structure toward a region of energy degeneracy with the ground state, from which the subsequent decay along the ground state hypersurface can lead to the photoreaction.

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Publication details

The article was received on 30 Sep 2017, accepted on 24 Oct 2017 and first published on 24 Oct 2017


Article type: Paper
DOI: 10.1039/C7FD00202E
Citation: Faraday Discuss., 2017, Accepted Manuscript
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    Photoinduced Formation Mechanism of the Thymine-Thymine (6-4) Adduct in DNA; a QM(CASPT2//CASSCF):MM(AMBER) study

    A. Giussani, I. Conti, A. Nenov and M. Garavelli, Faraday Discuss., 2017, Accepted Manuscript , DOI: 10.1039/C7FD00202E

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