QM/MM Study of the Uracil DNA Glycosylase Reaction Mechanism: A Competition between Asp145 and His148

Naydenova, Eli; Rossbach, Sven und Ochsenfeld, Christian (2019): QM/MM Study of the Uracil DNA Glycosylase Reaction Mechanism: A Competition between Asp145 and His148. In: Journal of Chemical Theory and Computation, Vol. 15, No. 8: pp. 4344-4350

Abstract

Uracil DNA glycosylase catalyzes the N-glycosidic bond cleavage of uracil, thereby initiating the base excision repair mechanism for this DNA lesion. Here we employ hybrid quantum mechanics/molecular mechanics calculations to investigate the exact mechanism of the nucleophile attack and the role of the conserved His148 residue. Our calculations suggest that the C1'-N1 bond dissociation proceeds by a migration of the electrophilic sugar in the direction of the water nucleophile, resulting in a planar, oxocarbenium-like transition state. The subsequent nucleophile addition and proton transfer to a nearby base occur without a barrier. We assign the role of a proton acceptor to His148 and elucidate why mutations of this residue curtail the enzymatic activity but do not fully suppress it.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Chemistry
• Subjects: 500 Science > 540 Chemistry
• ISSN: 1549-9618
• Language: English