Insights into Light‐driven DNA Repair by Photolyases: Challenges and Opportunities for Electronic Structure Theory

Abstract

Ultraviolet radiation causes two of the most abundant mutagenic and cytotoxic DNA lesions: cyclobutane pyrimidine dimers and 6-4 photoproducts. (6-4) Photolyases are light-activated enzymes that selectively bind to DNA and trigger repair of mutagenic 6-4 photoproducts via photoinduced electron transfer from flavin adenine dinucleotide anion (FADH À ) to the lesion triggering repair. This review provides an overview of the sequential steps of the repair process, that is light absorption and resonance energy transfer, photoinduced electron transfer and electron-induced splitting mechanisms, with an emphasis on the role of theory and computation. In addition, theoretical calculations and physical properties that can be used to classify specific mechanism are discussed in an effort to trace the fundamental aspects of each individual step and assist the interpretation of experimental data. The current challenges and suggested future directions are outlined for each step, concluding with a view on the future.

Photolyase: Dynamics and electron-transfer mechanisms of DNA repair

“…11E are triggered by the excitation of only one initial photon, which has also been supported by theoretical calculations [104, 107, 108, 113]. Recently, a two-photon repair mechanism of 6-4PP was suggested [111] by experiment [110] and some theoretical work [109].…”

“…Also, a two-photon repair mechanism has been proposed [110, 111]. Various theoretical calculations were carried out and several repair models have been suggested [104, 107–109, 112, 113]. Most of these proposed models invoke one proton transfer from a neighboring histidine residue at the active site (Fig.…”

Two aspartate residues close to the lesion binding site of Agrobacterium (6‐4) photolyase are required for Mg2+ stimulation of DNA repair

“…Several studies on (6-4) photolyases suggest that proton transfer occurs from this histidine residue to the damaged DNA as part of the repair process and that this residue is protonated in the ground state [23] and deprotonated for 10 ns or longer [24][25][26][27]. Other works support the hypothesis of a deprotonated active site histidine in the ground state and another reaction mechanism in (6-4) photolyases (for a review of the different mechanisms see [28]). For our studies on the localization of Mg 2+ , we consequently carried out two sets of simulations, one with positively charged His366 + and one with a neutral His366.…”

Photolyase: Dynamics and Mechanisms of Repair of Sun‐Induced DNA Damage

“…Also, a two‐photon repair mechanism has been proposed , which is also reviewed in this special issue . Various theoretical calculations were carried out and several repair models have been suggested (), including one also reviewed in this issue . Most models invoke one proton transfer from a neighboring histidine residue at the active site (Fig.…”

“…The dynamics of the branched FADH • in the repair channel (dashed light blue in Fig. C) exhibits a complex formation and a slow decay , but the amplitude is mainly determined by the repaired channel branching. By deconvolution, we obtained the BET2 in 57 ps and the repair channel in 481 ps to form a 6‐4PP •– ‐related intermediate.…”