title: Combined QM/MM investigation on the light-driven electron-induced repair of the (6-4) thymine dimer catalyzed by DNA photolyase.
abstract: The (6-4) photolyases are blue-light-activated enzymes that selectively bind to DNA and initiate splitting of mutagenic thymine (6-4) thymine photoproducts (T(6-4)T-PP) via photoinduced electron transfer from flavin adenine dinucleotide anion (FADH(-)) to the lesion triggering repair. In the present work, the repair mechanism after the initial electron transfer and the effect of the protein/DNA environment are investigated theoretically by means of hybrid quantum mechanical/molecular mechanical (QM/MM) simulations using X-ray structure of the enzyme-DNA complex. By comparison of three previously proposed repair mechanisms, we found that the lowest activation free energy is required for the pathway in which the key step governing the repair photocycle is electron transfer coupled with the proton transfer from the protonated histidine, His365, to the N3' nitrogen of the pyrimidone thymine. The transfer simultaneously occurs with concerted intramolecular OH transfer without formation of an oxetane or isolated water molecule intermediate. In contrast to previously suggested mechanisms, this newly identified pathway requires neither a subsequent two-photon process nor electronic excitation of the photolesion.
authors.affiliation: Interdisciplinary Center for Scientific Computing, Ruprecht-Karls University, Im Neuenheimer Feld 368, 69120 Heidelberg, Germany. shirin.faraji@uni-heidelberg.de
authors.forename: Shirin
authors.initials: S
authors.lastname: Faraji
authors.forename: Gerrit
authors.initials: G
authors.lastname: Groenhof
authors.forename: Andreas
authors.initials: A
authors.lastname: Dreuw
mesh_terms: D000818:Animals; D055162:Biocatalysis; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair; D004255:Deoxyribodipyrimidine Photo-Lyase / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology; D004579:Electron Transport; D004583:Electrons; D008027:Light; D008958:Models, Molecular; D011522:Protons; D011740:Pyrimidine Dimers / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory
chemical_list: D011522:Protons; D011740:Pyrimidine Dimers; D004247:DNA; D004255:Deoxyribodipyrimidine Photo-Lyase