Structural Insight into the Discrimination between 8‑Oxoguanine Glycosidic Conformers by DNA Repair Enzymes: A Molecular Dynamics Study of Human Oxoguanine Glycosylase 1 and Formamidopyrimidine-DNA Glycosylase

hOgg1 and FPG are the primary DNA repair enzymes responsible for removing the major guanine (G) oxidative product, namely, 7,8-dihydro-8-oxoguanine (OG), in humans and bacteria, respectively. While natural G adopts the <i>anti</i> conformation and forms a Watson–Crick pair with cytosine (C), OG can also adopt the <i>syn</i> conformation and form a Hoogsteen pair with adenine (A). hOgg1 removes OG paired with C but is inactive toward the OG:A pair. In contrast, FPG removes OG from OG:C pairs and also exhibits appreciable (although diminished) activity toward OG:A pairs. As a first step toward understanding this difference in activity, we have employed molecular dynamics simulations to examine how the <i>anti</i> and <i>syn</i> conformers of OG are accommodated in the hOgg1 and FPG active sites. When <i>anti-</i>OG is bound, hOgg1 active site residues are properly aligned to initiate catalytic base departure, while geometrical parameters required for the catalytic reaction are not conserved for <i>syn-</i>OG. On the other hand, the FPG catalytic residues are suitably aligned for both OG conformers, with <i>anti-</i>OG being more favorably bound. Thus, our data suggests that the differential ability of hOgg1 and FPG to accommodate the <i>anti</i>- and <i>syn</i>-OG glycosidic conformations is an important factor that contributes to the relative experimental excision rates. Nevertheless, the positions of the nucleophiles with respect to the lesion in the active sites suggest that the reactant complex is poised to initiate catalysis through a similar mechanism for both repair enzymes and supports a recently proposed mechanism in which sugar-ring opening precedes nucleoside deglycosylation