DNA repair mechanism by photolyase: Electron transfer path from the photolyase catalytic cofactor FADH(-) to DNA thymine dimer

Photolyase is an enzyme that catalyses photorepair of thymine dimers in UV damaged DNA by electron transfer reaction. The structure of the photolyase/ DNA complex is unknown at present. Using crystal structure coordinates of t he substrate-free enzyme from E. coil, we have recently built a computer mo lecular model of a thymine dimer docked to photolyase catalytic site and st udied molecular dynamics of the system. In this paper, we present analysis of the electronic coupling and electron transfer pathway between the cataly tic cofactor FADH(-) and the pyrimidine dimer by the method of interatomic tunneling currents. Electronic structure is treated in the extended Huckel approximation. The root mean square transfer matrix element is about 6 cm(- 1), which is consistent with the experimentally determined rate of transfer . We find that electron transfer mechanism responsible for the repair utili zes an unusual folded conformation of FADH- in photolyases, in which the is oalloxazine ring of the flavin and the adenine are in close proximity, and the peculiar features of the docked orientation of the dimer. The tunneling currents show explicitly that despite of the close proximity between the d onor and acceptor complexes, the electron transfer mechanism between the fl avin and the thymine bases is not direct, but indirect, with the adenine ac ting as an intermediate. These calculations confirm the previously made con clusion based on an indirect evidence for such mechanism. (C) 2001 Academic Press.