Theoretical study of electron transfer between the photolyase catalytic cofactor FADH(-) and DNA thymine dimer

Photolyase is an enzyme that catalyzes photorepair of thymine dimers in UV damaged DNA by electron-transfer reaction. We docked a thymine dimer to pho tolyase catalytic site, using crystal structure coordinates of the substrat e-free enzyme from Escherichia coli, studied molecular dynamics of the syst em, and calculated the electron-transfer matrix element between the lowest unoccupied molecular orbitals of flavin and the dimer. We find that the rms transfer matrix element along the dynamic trajectory is about 6 cm(-1) whi ch is consistent with the experimentally determined rate of transfer. In th e average configuration the docked thymine dimer is sitting deep in the cat alytic site, and approaches the adenine of FAD with the C4=O4 carbonyl grou ps. The average distance between the flavin and the base pair is less than 3 A. The electron-transfer mechanism utilizes the unusual conformation of F AD in photolyases, in which the isoalloxazine ring of the flavin and the ad enine are in close proximity, and the peculiar features of the docked orien tation of the dimer. The calculations show that despite the short distance between the donor and acceptor complexes, the electron-transfer mechanism b etween the flavin and the thymine bases is not direct, but indirect, with t he adenine acting as an intermediate.