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.
Invited for the cover of this issue is the group of Robert S. Paton at the University of Oxford and his collaborators from Brazil and the Czech Republic. The image depicts histone–enzyme complexation and the chemical interactions inside the active site that define the mode of action. Read the full text of the article at .
Before trimethylated lysines can be epigenetically “erased”, molecular oxygen must be bound into the active site of JmjC proteins. This work sheds new computational understanding on the role of the wider protein environment in making this process possible. In the foreground of the cover illustration by Dr Karl Harrison an atomistic description of this complex is shown, while in the background these proteins can be seen interacting with the DNA bound histones. For more details see the Full Paper on by R. S. Paton and co‐workers.
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