CODECS 2013 Workshop. San Lorenzo de El Escorial, Madrid, 18th –22nd April, 2013
Proton-Transfer-Steered Mechanism of Photolesion Repair by (6-4)
Photolyases
Shirin Faraji and Andreas Dreuw
Theoretical and Computational Chemistry, Interdisciplinary Center for Scientific Computing
(IWR), Heidelberg University, INF 368, D-69120 Heidelberg, Germany
[email protected]
Several strategies have evolved to repair one of the most abundant UV radiation-induced
damages of DNA, the (6-4) photoproduct (PP). DNA (6-4)-photolyases are enzymes initiating
cleavage of mutagenic pyrimidine (6-4) pyrimidone photolesions by a photoinitiated electron
transfer from flavin adenine dinucleotide to the lesion [1]. Recently, it has been revealed that the
repair mechanism occurs in the electronic ground state of the lesion radical anion, since the
initially absorbed photon energy is not sufficient to initiate electron transfer and to
simultaneously electronically excite the radical anion of the (6-4)-PP [2]. Using state-of-the-art
quantum chemical calculations on a reduced molecular model in the gas phase, we have
presented the first energetically feasible molecular repair mechanism [3]. In this presentation, the
repair mechanism after the initial electron transfer is explored by means of hybrid quantum
mechanical/molecular mechanical (QM/MM) dynamics simulations based on the X-ray structure
of the enzyme-DNA complex, to shed further light onto the influence of the protein environment
and to cover related issues of protein/DNA interaction. In agreement with our previously
proposed mechanism, the initial step is electron transfer coupled to proton transfer from the
protonated His365 to the N3′ nitrogen of the pyrimidone thymine of the lesion, which proceeds
simultaneously with intramolecular OH transfer in a concerted reaction without formation of an
oxetane or isolated water molecule intermediate. This newly identified pathway requires neither a
two-photon process nor electronic excitation of the photolesion. Our theoretical findings are in
agreement with recent experimental findings [4].
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Fig. 1. Schematic representation of the overall repair mechanism of DNA photolyase
References
1. S. Weber, Biochim. Biophys. Acta. 1707, 1-23 (2005).
2. P. Harbach , J. Borowka, M. Bohnwagner, A. Dreuw, J. Phys. Chem. Lett. 1, 2556 (2010).
3. S. Faraji and A. Dreuw, J. Phys. Chem. Lett. 3, 227 (2012).
4. J. Li, Z. Liu, C. Tan, X. Guo, L. Wang, A. Sancar, D. Zhong, Nature 466, 887 (2010).