Electron-Transfer Induced Repair of 6-4 Photoproducts in DNA:  A Computational Study

Abstract

The mechanism employed by DNA photolyase to repair 6-4 photoproducts in UV-damaged DNA is explored by means of quantum chemical calculations. Considering the repair of both oxetane and azetidine lesions, it is demonstrated that reduction as well as oxidation enables a reversion reaction by creating anionic or cationic radicals that readily fragment into monomeric pyrimidines. However, on the basis of calculated reaction energies indicating that electron transfer from the enzyme to the lesion is a much more favorable process than electron transfer in the opposite direction, it is suggested that the photoenzymic repair can only occur by way of an anionic mechanism. Furthermore, it is shown that reduction of the oxetane facilitates a mechanism involving cleavage of the C-O bond followed by cleavage of the C-C bond, whereas reductive fragmentation of the azetidine may proceed with either of the intermonomeric C-N and C-C bonds cleaved as the first step. From calculations on neutral azetidine radicals, a significant increase in the free-energy barrier for the initial fragmentation step upon protonation of the carbonylic oxygens is predicted. This effect can be attributed to protonation serving to stabilize reactant complexes more than transition structures.

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.…”

Characterization of the Intermediate in and Identification of the Repair Mechanism of (6‐4) Photolesions by Photolyases

“…(Figure ). Experimental and theoretical studies have been performed intensively over the past years, to trace all steps of the repair. While the functional mechanism of CPD photolyases has been identified, the details of the repair mechanism operating in (6‐4) photolyases is still a matter of ongoing debate.…”

Hetero-cycloreversions Mediated by Photoinduced Electron Transfer

“…22,23,24,25,26,27 The idea that (6-4) photoproducts are converted to oxetanes (or azetidines) upon binding to the enzyme in the dark has been questioned based on the crystal structure of a model (6-4) photoproduct in the binding pocket. 28,29 In general, experimental and theoretical studies assume that (6-4) photoproducts are repaired upon absorption of a single photon by the enzyme.…”

“…The PET CR of azetidines has also been the subject of experimental and theoretical work related to 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 UVB-induced DNA repair. 25,26 Moreover, the generation and fate of azetidine radical ions in the gas phase has been reported in the course of mass spectrometric studies. 55 Reaction of cis-and trans-1,2,3-triphenylazetidine with BAHA as ET-oxidizing agent leads to cis-and trans-stilbene, together with N-benzylideneaniline.…”