Photolyase is a DNA repair enzyme, which splits thymine dimers in UV-damaged DNA by photoinduced electron transfer between photolyase cofactor FADH- and the dimer of DNA. Recently, the crystal structure of the DNA/Photolyase complex has been solved, confirming an earlier prediction that upon the enzyme binding, DNA locally melts, the dimer flips out of the DNA helix and approaches the FADH cofactor within a three- angstrom distance. The resolved structure of the photolyase/DNA complex, together with state-of-the-art computer simulations, open up a unique opportunity to gain atomic-scale insights into some of the key mechanisms by which cells maintains stability of their genomes. Building upon the most recent X-ray structural data and previous modeling, using advanced computational techniques developed earlier, the group will investigate different aspects of photorepair of thymine dimers by photolyase. Specific aims include a study of the mechanism of electron transfer between the enzyme FADH redox co-factor and the thymine dimer of DNA; the repair reaction itself, in which the dimer splits; the mechanism by which photolyase finds the dimer on DNA; and the mechanism by which the dimer flips out of the DNA helix in the process of complex formation and dimer recognition. Computer simulations play an ever increasing role in the process of biological discovery. As the themes of the project cut across such areas as cancer, cell aging, gene regulation, biological rhythms, and molecular evolution, the computational research in this project provides an exceptionally rich training ground for a team of a postdoc, grad student, and an undergraduate involved in this work.
