DNA glycosylase, as one member of the DNA repair machineries, plays an essential role in correcting mismatched/damaged DNA base pair by cleaving the N-glycosidic bond between the sugar and target base through the base excision repair (BER) pathways. Efficient corrections of these DNA lesions are critical for maintaining genome integrity and preventing premature aging and cancer. The target-site searching and recognition mechanism by DNA glycosylase, however, remains unknown and experimental characterization of the above process is still challenging due to the limited spatiotemporal resolutions. In this work, by employing high performance computing, combined with markov state model construction based on extensive all-atom molecular dynamics (MD) simulations, we capture several critical intermediate states of the mispaired dT nucleotide during its extrusion process and identify several key TDG residues that are directly involved in the inter-state transitions. Moreover, our studies reveal the atomistic-level details of how TDG participates in sculpturing the DNA backbone and penetrates into the DNA minor groove. Finally, we extended our studies to three additional TDG substrates (dU, 5fC, and 5caC) to evaluate the substituent effects of various chemical modifications of the pyrimidine rings on the base-flipping dynamics.

Computational investigations on target-site searching and recognition mechanism by thymine DNA glycosylase during DNA repair process

2019 Spring National Meeting

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