![Author ORCID: We display the ORCID iD icon alongside authors names on our website to acknowledge that the ORCiD has been authenticated when entered by the user. To view the users ORCiD record click the icon. [opens in a new tab]](https://chemrxiv.org/engage/assets/public/chemrxiv/images/logos/orcid.png)
Abstract
The harmful pyrimidine-pyrimidone (6-4) lesions in DNA are repaired by a specific photoenzyme DNA 6-4 photolyase (64PL). The repair process combines photoexcitation of the FADH− cofactor with electron transfer (ET) and proton transfer (PT) reactions. Despite being researched for three decades, the chemical details of the lesion reversion to the intact nucleobases are far from being clear. Here we investigate a commonly anticipated PT reaction from a conserved histidine residue to the 3’base of the lesion. Employing quantum chemistry calculations and molecular dynamics simulations of the 64PL enzyme from Dr. Melanogaster we estimate energies of PT and ET reactions involving His365. The results suggest that PT from His365 to the 3’base is energetically favourable whereas ET from the FADH− cofactor to the 3’base is disfavoured by the low electronic coupling. The anticipated spontaneous deprotonation of His365 upon lesion binding to the enzyme clearly suggests that 3’ base protonation by His365 does not belong to the lesion repair pathway.
