Cycloreversion of the (6-4) photolesion: DFT studies of the DNA repair mechanism

COMP 220

Chris Harrison, charris5@nd.edu and Olaf Wiest, owiest@nd.edu. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670
Formation of the (6-4) photolesion, 1, damages genetic information, leading ultimately to skin cancer and cell death. Through an unknown mechanism, 1 may be repaired in vivo by (6-4) photolyase. In absence of an x-ray structure of (6-4) photolyase and the instability of the proposed oxetane intermediate, 2, the currently proposed mechanism cannot be validated. Mapping of the potential energy surface using hybrid DFT calculations indicates a barrierless reaction from 2- to two thymine monomers, 3. As suggested by Todo et al., the presence of a hydrogen donor and acceptor also results in a barrierless cycloreversion of 2- to 3. The formation of 2 from 1 is 15.5 kcal/mol uphill. It is thus difficult to rationalize thermal formation of 2 from 1, followed by electron transfer catalyzed cycloreversion yielding two thymine monomers, 3. Given these concerns, the currently proposed and alternative mechanistic pathways will be investigated via gas phase and solution DFT calculations.