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Report No.

Theoretical study of the human DNA repair protein HOGG1 activity

Schyman, P.*; Danielsson, J.*; Pinak, M.; Laaksonen, A.*

We have examined the role of the catalytic lysine (Lys 249) in breaking the glycosidic bond of 8-oxoguanine in the enzyme human 8-oxoguanine DNA glycosylase. It has been assumed that this lysine acts as a nucleophile in a S$$_{N}$$2 type of reaction after being activated through a donation of a proton to a strictly conserved aspartate. We use hybrid density functional theory to characterize both associative and dissociative pathways. We find that the smallest energetical barrier involves a S$$_{N}$$1 type of mechanism where the lysine electrostatically stabilizes the dissociating base and then donates a proton with a very small barrier and then finally attacks the sugar ring to create the covalently bounded protein-DNA intermediate complex. Reported findings give further support to the assumption that a dissociative mechanism may be the preferred mode of action for this type of enzymes.



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Category:Chemistry, Physical



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