The non-heme Fe(II) and 2-Oxoglutarate (2OG)-Dependent Histone Demethylases (KDMs) are responsible for demethylation of methylated lysine residues in histone proteins. The dynamic changes in the methylation status of histones is one of the key epigenetic mechanisms that regulate the transcription of DNA. KDMs are related with various cancers, including prostate, breast, laryngeal and hypopharyngeal, lung, bladder, gastric, and endometrial carcinoma as well as inherited mental retardation and therefore they are targets for drug design efforts. While experimental studies provided important knowledge regarding KDMs structure, binding and kinetics, still there are missing information about their reaction mechanisms, and how the dynamics influences the interactions between the non-heme iron center and protein residues in KDMs. To complete the missing knowledge, we performed comprehensive multiscale computational studies of two KDMs - KDM4A and KDM7B (PHF8) using MD and QM/MM methods. The study revealed the reaction mechanisms of the both enzymes with focus on the Molecular Orbitals control, conformational and mutational effects. The dioxygen activation step, H-abstraction by Fe(IV)=O intermediate, and the rebound hydroxylation steps have been explored. Furthermore, we analyzed some alternative mechanistic proposals. The study analyzed the effects of second-sphere mutations on the reaction mechanism and energetics. The binding of the histone substrate and non-histone macrocyclic peptides was studied with focus on their influence on the non-heme iron center and the protein structure.

Non-heme iron and 2-oxogluatarate-dependent histone demethylases: Understanding reaction mechanisms, ligand binding and dynamics using QM/MM and MD methods

2019 Fall National Meeting

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