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 a consecutive thymine nucleobase in a DNA strand to form the thymine-thymine (6-4) photodamage adduct remains poorly understood. Key questions remain unanswered, concerning both the intrinsic features of the photoreaction (such as the contribution (or not) of triplet states, the nature of the involved states and the time-scale of the photoprocess) and the role played by the non-reactive surroundings of the two reactive pyrimidine nucleobases (such as the nature of the flanked nucleobases and the flexibility of the whole DNA molecule). A small number of theoretical studies have been carried out on the title photoreaction, most of which have used reduced model systems of DNA, consequently neglecting potential key parameters for the photoreaction such as the constraints due to the double strain structure and the presence of paired and stacked nucleobases. In the present contribution the photoactivation 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 photodamage formation has been recently experimentally measured. The reaction has been characterized by carrying out 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 has been characterized, the nature of the reactive states has 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, thus substantially contributing towards the elucidation of the photoreaction mechanism. On the basis of the obtained results, it can be observed that a charge-transfer state can decay from a pro-reactive initial structure towards a region of energy degeneracy with the ground state, from which the subsequent decay along the ground state hypersurface can lead to the photoreaction.

A Unified Experimental/Theoretical Description of the Ultrafast Photophysics of Single and Double Thionated Uracils

“…The TA spectra and the decay paths were modeled by COBRAMM, our hybrid QM/MM scheme, [29,[41][42][43][44][45][46][47] that couples high level ab initio multireference dynamically correlated methods (CASPT2// CASSCF) [48] of the photoactive thiouracil system with an explicit classical atomistic model (Amber force field) [49,50] of the solvent (see Supporting Information for more details). An High/Medium/Low layers partitioning was applied to as pherical droplet centered at 2TU and 24TU with ar adius of 12 (containing 261 and 265 waters), obtained from the cubic box.…”

Detection of the thietane precursor in the UVA formation of the DNA 6-4 photoadduct

“…However, the authors were unable to experimentally detect the oxetane intermediate 33 , and only computational predictions supported its participation in the formation of the (6–4) photoadduct in the xylene-thymine dinucleotide. Furthermore, the redox properties of meta-xylene are significantly different from those of thymine, favoring a complete electron transfer pathway in this dinucleotide analog 33 relative to a partial charge-transfer pathway thymine–thymine dinucleotide 18 – 20 .

Fig.

…”

Quantum Chemical Modeling of the Photoinduced Activity of Multichromophoric Biosystems

“…More accurate, but expensive, multireference perturbative approaches have been also employed although mostly limited to QM dimers. 142,147,149,150…”

“…160 Dimerization reactions also occur for specific configurations, showing that the evolution of delocalized Frenkel exciton states may branch into different intra- and interbase decay paths, including CT states. 150,161…”