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

Abstract

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 anti conformation and forms a Watson-Crick pair with cytosine (C), OG can also adopt the syn 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 anti and syn conformers of OG are accommodated in the hOgg1 and FPG active sites. When anti-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 syn-OG. On the other hand, the FPG catalytic residues are suitably aligned for both OG conformers, with anti-OG being more favorably bound. Thus, our data suggests that the differential ability of hOgg1 and FPG to accommodate the anti- and syn-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.

Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity

“…OGG1 is well characterized structurally, with an extensive set of X-ray structures illuminating its catalytic cycle from the discrimination between normal and damaged DNA to the post-excision steps (43,44,(56)(57)(58)(59)(60)(61)(62)(63)(64). Based on these structures, several MD and QM/MM exercises were attempted to investigate the process of dynamic damaged base recognition (45,46,(65)(66)(67) and catalytic steps (58,(68)(69)(70)(71)(72). Experimental consequences of many site-directed mutations were characterized as part of mechanistic studies on OGG1 activity (43)(44)(45)(46)62,73,74).…”

Computational studies of DNA repair: Insights into the function of monofunctional DNA glycosylases in the base excision repair pathway

“…To complement several reviews that have focused on experimental studies of BER enzymes (see, for example, references ) and to highlight key information provided from computer modeling, this Focus Article provides a mini‐review of computational studies of the chemical step facilitated by a selection of monofunctional DNA glycosylases. Although we acknowledge that several important computational works have examined the function of bifunctional DNA glycosylases (such as hOgg1, FPG and NEIL1), we focus herein on the challenge associated with hydrolysis of DNA glycosidic bonds. Furthermore, we emphasize the contributions of computational chemistry in deciphering the chemical step facilitated by several glycosylases, while recognizing that the base flipping step is also an important function of these repair enzymes and other computational work has shed light on this aspect of BER, including why some glycosylases do not base flip (AlkD) .…”

Strategies of N-Glycosidic Bond Cleavage by Dna Repair Enzymes

“…В ДНК oxodGuo, как и dGuo, существует в анти-конформации, но в отсутствие канонических уотсон-криковсих связей переходит в синконформацию из-за невыгодных стерических взаимодействий атома O 8 с 5′-фосфатом. Во всех экспериментально определенных структурах комплексов OGG1-ДНК oxodGuo находится в анти-конформации, и только в ней реакция может протекать [50] [54,55]. Однако ряд структур, имитирующих интермедиаты реакции, в совокупности с определением стереохимии продуктов их метанолиза и кинетики высвобождения продуктов реакции недавно позволили предложить принципиально новый вариант механизма S N 1, ранее вообще не рассматривавшийся для ДНК-гликозилаз [56][57][58].…”