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This study investigates dioxygen binding and 2-oxoglutarate (2OG) coordination by two model non-heme Fe(II)/2OG enzymes: a class 7 histone demethylase (PHF8) that catalyzes the hydroxylation of its H3K9me2 histone substrate leading to demethylation reactivity and the ethylene-forming enzyme (EFE) that catalyzes two competing reactions of ethylene generation and substrate L-Arg hydroxylation. Although both enzymes initially bind 2OG using an off-line 2OG coordination mode, in PHF8, the substrate oxidation requires a transition to an in-line mode, whereas EFE is catalytically productive for ethylene production from 2OG via the off-line mode. We utilized classical molecular dynamics, quantum mechanics/molecular mechanics (QM/MM) MD and QM/MM metadynamics simulations to reveal that it is the dioxygen binding process and, ultimately, the protein environment that control the formation of the in-line Fe(III)-OO-. intermediate in PHF8 and the off-line Fe(III)-OO-. intermediate in EFE.

Original publication




Journal article



Publication Date



Dioxygen Diffusion, QM/MM, MD, EFE, Histone Demethylases, PHF8