Photoselected electron transfer pathways in DNA photolyase

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Abstract
Cyclobutane dimer photolyases are proteins that bind to UV-damaged DNA containing cyclobutane pyrimidine dimer lesions. They repair these lesions by photo-induced electron transfer. The electron donor cofactor of a photolyase is a two-electron-reduced flavin adenine dinucleotide (FADH − ). When FADH − is photo-excited, it transfers an electron from an excited π → π* singlet state to the pyrimidine dimer lesion of DNA. We compute the lowest excited singlet states of FADH − using ab initio (time-dependent density functional theory and time-dependent Hartree–Fock), and semiempirical (INDO/S configuration interaction) methods. The calculations show that the two lowest π → π* singlet states of FADH − are localized on the side of the flavin ring that is proximal to the dimer lesion of DNA. For the lowest-energy donor excited state of FADH − , we compute the conformationally averaged electronic coupling to acceptor states of the thymine dimer. The coupling calculations are performed at the INDO/S level, on donor–acceptor cofactor conformations obtained from molecular dynamics simulations of the solvated protein with a thymine dimer docked in its active site. These calculations demonstrate that the localization of the 1 FADH − * donor state on the flavin ring enhances the electronic coupling between the flavin and the dimer by permitting shorter electron-transfer pathways to the dimer that have single through-space jumps. Therefore, in photolyase, the photo-excitation itself enhances the electron transfer rate by moving the electron towards the dimer.