JMJD2A is a histone demethylase and a molecular target for the development of new anti-cancer drugs. The detailed mechanism of demethylation is yet not fully understood and may play a key role for the understanding of epigenetic processes. In this work, we have evaluated the mechanism of the O2 binding in histone demethylases using a combination of classical Molecular Dynamics (MD), quantum mechanics (QM) and quantum mechanics/molecular mechanics (QM/MM) calculations. QM calculations were performed with the dispersion corrected DFT-D3 method and the Amber force field was used for MD. We examined a different selection of exchange-correlation functionals employing the Generalized Gradient Approximation (GGA), including B3LYP, B3PW91 and BP86 functionals, and the hybrid meta-GGA functional M06. We found the oxygen binding to happen preferentially on the quintet potential energy surface for four of the five analysed functionals, with O2 in a so-called “end-on” conformation and oxidation of FeII to FeIII. This binding mode is favoured by sizable electrostatic energy contributions and dispersion effects due to the methylated lysine, which suggests that the substrate may be bound in the active site before O2, in agreement with experimental data. Glu184 and the oxoglutarate cofactor are deleterious for O2 binding, mainly because of unfavourable electrostatic interactions. Asp187 and Arg233 had favorable and unfavourable contributions to the O2 binding, respectively, and they both interacted with Glu184 through a hydrogen bonds network. Our results showed the first step of the demethylation reaction in JMJD2A to be exergonic, even after considering the strong unfavourable entropic effects.[1] We demonstrate the importance of the extended protein environment in oxygen binding, and the role of energy decomposition in understanding the physical origin of binding/recognition. In addition, we propose mutation hot-spots in JMJD2A proteins which may impact the demethylation reaction. [1] Cortopassi, W. A. et al. Chem. Eur. J. 2015. In press.

Role of the protein environment for the O2 binding in the active site of histone demethylase JMJD2A

251st National Meeting (2016)

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