Insights into conformational changes in AlkD bound to DNA with a yatakemycin adduct from computational simulations

Structural integrity of DNA molecules is necessary for their information storage function. Cells rely on a number of pathways to ensure that the damage to DNA induced by endogenous and exogenous reagents is repaired. AlkD, a base excision enzyme, removes a damaged nucleobase by cleaving a glycosidic bond. Unlike many other base excision enzymes, AlkD does not flip a damaged nucleobase into a designated reaction pocket, and as such can repair nucleobases with larger adducts, such as yatakemycin. In this study, the structure and dynamics of AlkD have been investigated by classical molecular dynamics simulations. Several systems including apo-AlkD, and AlkD in complex with DNA, both with and without the yatakemycin adduct have been simulated. Comparison of the results for the apo-AlkD with AlkD with substrate (damaged or undamaged) indicates a high degree of motion of helix αB in apo-AlkD, whereas this helix is observed to form various contacts when the substrate is bound. The calculated results are consistent with previous experimental studies that have suggested various residues involved in damage recognition, DNA binding, and base excision catalysis.