Volume 21, Issue 52 p. 18983-18992
Full Paper

Dioxygen Binding in the Active Site of Histone Demethylase JMJD2A and the Role of the Protein Environment

Wilian A. Cortopassi

Wilian A. Cortopassi

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA (UK) paton.chem.ox.ac.uk

Physical and Theoretical Chemistry Laboratory, South Parks Road, Oxford OX1 3QZ (UK)

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Robert Simion

Robert Simion

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA (UK) paton.chem.ox.ac.uk

Physical and Theoretical Chemistry Laboratory, South Parks Road, Oxford OX1 3QZ (UK)

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Charles E. Honsby

Charles E. Honsby

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA (UK) paton.chem.ox.ac.uk

Physical and Theoretical Chemistry Laboratory, South Parks Road, Oxford OX1 3QZ (UK)

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Prof. Tanos C. C. França

Prof. Tanos C. C. França

Department of Chemical Engineering, Military Institute of Engineering, 80 Praça General Tibúrcio, Urca, 22290 270, Rio de Janeiro (Brazil)

Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove (Czech Republic)

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Prof. Robert S. Paton

Corresponding Author

Prof. Robert S. Paton

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA (UK) paton.chem.ox.ac.uk

Physical and Theoretical Chemistry Laboratory, South Parks Road, Oxford OX1 3QZ (UK)

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA (UK) paton.chem.ox.ac.ukSearch for more papers by this author
First published: 18 November 2015
Citations: 16

Graphical Abstract

Environmental appreciation: The consideration of protein residues during QM/MM calculations for the O2 binding in lysine’s demethylation inside JMJD2A resulted in an energetically favourable process (see figure), with the oxidation of FeII to FeIII in the quintet overall spin state, driven by dispersion effects and electrostatic and van der Waals interactions. These contributions ensure exergonic O2 binding in the family of demethylase proteins.

Abstract

JMJD2A catalyses the demethylation of di- and trimethylated lysine residues in histone tails and is a target for the development of new anticancer medicines. Mechanistic details of demethylation are yet to be elucidated and are important for the understanding of epigenetic processes. We have evaluated the initial step of histone demethylation by JMJD2A and demonstrate the dramatic effect of the protein environment upon oxygen binding using quantum mechanics/molecular mechanics (QM/MM) calculations. The changes in electronic structure have been studied for possible spin states and different conformations of O2, using a combination of quantum and classical simulations. O2 binding to this histone demethylase is computed to occur preferentially as an end-on superoxo radical bound to a high-spin ferric centre, yielding an overall quintet ground state. The favourability of binding is strongly influenced by the surrounding protein: we have quantified this effect using an energy decomposition scheme into electrostatic and dispersion contributions. His182 and the methylated lysine assist while Glu184 and the oxoglutarate cofactor are deleterious for O2 binding. Charge separation in the superoxo-intermediate benefits from the electrostatic stabilization provided by the surrounding residues, stabilizing the binding process significantly. This work demonstrates the importance of the extended protein environment in oxygen binding, and the role of energy decomposition in understanding the physical origin of binding/recognition.