Key structural motifs in Thymine DNA glycosylase responsible for recognizing certain DNA bent conformation revealed...

Knowledge of how DNA bending facilitates the target-base searching by Thymine DNA glycosylase (TDG) is of major importance for unraveling the recognition mechanism between DNA and TDG in DNA repair process. An atomic-level understanding of the initial encounter between TDG and DNA before base-flipping, however, is still elusive. Here, we employ all-atom molecular dynamics (MD) simulations with an integrated simulation time of ∼3 μs to investigate how TDG responses to different DNA bending conformations. By constructing several TDG-DNA complexes with varied DNA bend angles (ranging from ∼0° to 60°), we pinpoint the key TDG motifs responsible for recognizing certain DNA bending conformations. Particularly, several positively charged residues, i.e., Lys232, Lys240, and Lys246, are critical for the tight binding with DNA backbones. Importantly, the roll-angle patterns, rather than the tilt and twist angles, are found to be strongly correlated with the extent of DNA bending, which in turn, governs the TDG recognition. Further comparisons between the naked and TDG-bound DNA conformations reveal that the TDG binding can impose a substantial DNA deformation, resulting in profound roll-angle alterations. Our studies warrant further experimental validations and provide deep structural insights into the recognition mechanism between TDG and DNA during their initial encounter.