Multiple Electronic and Structural Factors Control Cyclobutane Pyrimidine Dimer and 6–4 Thymine–Thymine Photodimerization in a DNA Duplex

Abstract

The T-T photodimerization paths leading to the formation of cyclobutane pyrimidine dimer (CPD) and 6-4 pyrimidine pyrimidone (64-PP), the two main DNA photolesions, have been resolved for a T-T step in a DNA duplex by two complementary state-of-the-art quantum mechanical approaches: QM(CASPT2//CASSCF)/MM and TD-DFT/PCM. Based on the analysis of several different representative structures, we define a new-ensemble of cooperating geometrical and electronic factors (besides the distance between the reacting bonds) ruling T-T photodimerization in DNA. CPD is formed by a barrierless path on an exciton state delocalized over the two bases. Large interbase stacking and shift values, together with a small pseudorotation phase angle for T at the 3'-end, favor this reaction. The oxetane intermediate, leading to a 64-PP adduct, is formed on a singlet T→T charge-transfer state and is favored by a large interbase angle and slide values. A small energy barrier (<0.3 eV) is associated to this path, likely contributing to the smaller quantum yield observed for this process. Eventually, a clear directionality is always shown by the electronic excitation characterizing the singlet photoactive state driving the photodimerization process: an exciton that is more localized on T and a 5'-T→3'-T charge transfer for CPD and oxetane formation, respectively, thus calling for specific electronic constraints.

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, that couples high level ab initio multireference dynamically correlated methods (CASPT2//CASSCF) of the photoactive thiouracil system with an explicit classical atomistic model (Amber force field) of the solvent (see Supporting Information for more details).…”

Linear absorption spectra of solvated thiouracils resolved at the hybrid RASPT2/MM level

“…3. QM/MM calculations: geometry refinement and electronic structure computations QM/MM calculations were performed with the COBRAMM suite developed in our group interfacing various QM codes with AMBER (presented in detail elsewhere [10,[74][75][76]). Prior to High/Medium/Low layer partitioning a spherical droplet centered at thiouracil with a radius of 12 Å (containing 260 waters in 2-thiouracil, 245 waters in 4thiouracil and 264 waters in 2,4-thiouracil) was cut from the cubic box.…”

Evolution of the Excitonic State of DNA Stacked Thymines: Intrabase ππ* → S0 Decay Paths Account for Ultrafast (Subpicosecond) and Longer (>100 ps) Deactivations

“…This is a realistic model of DNA considering that dimeric excitons dominate the photon absorption process 33 either in homo-and hetero-DNA multimers that show at least two stacked homo-bases. Four different intra-base ππ* decay routes accounts for all the possible classical 'ethene-like' mechanism, due to the asymmetric environment experienced by Thys in B-DNA 31,35 . Three of them roughly resemble the decay path energy profile found in isolated solvated nucleosides, showing a very flat decay path with a tiny barrier along the ring-puckering/methyl-bending reaction coordinate, and accounting for the two ultrafast (τ 1 and τ 2 ) decay components observed.…”

“…In the present Letter, we analyse how the classical monomer-like ππ*→S 0 decay paths (defined as 'ethene-like') of two stacked Thymines (Thys), and responsible for the ultrafast decays of the single solvated nucleobase [4][5][6]25 , are affected by the DNA environment leading to much longer excited state lifetimes. For this purpose, we employ the solvated double strand B-fragment 5'-C- (SI) 23,[31][32] ). Eventually, single point CASPT2//CASSCF(16,14)/MM calculations were performed to deliver realistic energies of the optimized critical points and Conical Intersections (CIs) (see the Computational Methods in the SI for more details).…”