jp401662z_si_001.pdf (593.42 kB)
Combined QM/MM Investigation on the Light-Driven Electron-Induced Repair of the (6–4) Thymine Dimer Catalyzed by DNA Photolyase
journal contribution
posted on 2013-09-05, 00:00 authored by Shirin Faraji, Gerrit Groenhof, Andreas DreuwThe (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.