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Computational investigation of the mechanism of action of DNA glycosylases
(Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry, 2013) Kellie, Jennifer L.; University of Lethbridge. Faculty of Arts and Science; Wetmore, Stacey D.
The integrity of the base pair sequence that makes up the information storage system of cells is under continual assault. Two of the most prevalent forms of nucleobase damage are conversion of cytosine to uracil, and guanine to 8-oxoguanine. Repair of these lesions is initiated by a specific glycosylase that hydrolyzes the N-glycosidic (sugar–nucleobase) bond of the damaged nucleotide. The present thesis uses advanced computational chemistry techniques to study the mechanism of action of three glycosylases, namely human uracil–DNA glycosylase (hUNG2), adenine–DNA glycosylase (MutY) and human 8-oxoguanine–DNA glycosylase (hOgg1). Truncated active-site models treated entirely with quantum mechanics, and reaction potential energy surfaces, provide detailed structural and energetic information regarding how these enzymes catalyze deglycosylation of their substrates. From these results, a novel and informative method for predicting the mechanism (e.g., degree of asychronicity) and relative rate is proposed.