Modeling of Electron and Proton Transfer in the Photocatalytic Repair of 6-4 DNA Photodimers

Abstract The photoenzyme 6-4 DNA photolyase catalyzes the repair of carcinogenic 6-4 DNA photodimers (64PDs) formed by adjacent pyrimidine bases in the DNA strand. This work is devoted to obtaining energy estimates for protonation reactions of 64PD proposed in the literature (using the thymine–thymine dinucleotide 5'T–3'T as an example) involving the conserved histidine residue of the active site of the photoenzyme before and after electron transfer to 64PD from the anionic hydroquinone form of the flavin adenine dinucleotide (FADH – ) cofactor. The energies of proton and electron transfer reactions were obtained using density functional theory calculations, multiconfigurational quantum chemical calculations, and molecular dynamics simulations of various protonated forms of the photoenzyme complex with the DNA substrate. Protonation of the 3'T fragment in 64PD by the histidine residue is energetically favorable and possibly occurs during the binding of the damaged DNA to the photoenzyme prior to its photoexcitation. Subsequent photoinduced electron transfer from the FADH – cofactor to the 3'T fragment yields a radical intermediate, ensuring a significant decrease in energy along this reaction coordinate. However, the obtained estimates qualitatively disagree with experimental data on the dynamics of the photoinduced repair of 6-4 DNA by photolyase. This excludes the participation of the conserved photolyase histidine residue in protonation of the 3'T fragment during the repair of 64PD.