Abstract
BackgroundHistone demethylase, JMJD2A, specifically recognizes and binds to methylated lysine residues at histone H3 and H4 tails (especially trimethylated H3K4 (H3K4me3), trimethylated H3K9 (H3K9me3) and di,trimethylated H4K20 (H4K20me2, H4K20me3)) via its tandem tudor domains. Crystal structures of JMJD2A-tudor binding to H3K4me3 and H4K20me3 peptides are available whereas the others are not. Complete picture of the recognition of the four histone peptides by the tandem tudor domains yet remains to be clarified.Methodology/Principal FindingsWe report a detailed molecular dynamics simulation and binding energy analysis of the recognition of JMJD2A-tudor with four different histone tails. 25 ns fully unrestrained molecular dynamics simulations are carried out for each of the bound and free structures. We investigate the important hydrogen bonds and electrostatic interactions between the tudor domains and the peptide molecules and identify the critical residues that stabilize the complexes. Our binding free energy calculations show that H4K20me2 and H3K9me3 peptides have the highest and lowest affinity to JMJD2A-tudor, respectively. We also show that H4K20me2 peptide adopts the same binding mode with H4K20me3 peptide, and H3K9me3 peptide adopts the same binding mode with H3K4me3 peptide. Decomposition of the enthalpic and the entropic contributions to the binding free energies indicate that the recognition of the histone peptides is mainly driven by favourable van der Waals interactions. Residue decomposition of the binding free energies with backbone and side chain contributions as well as their energetic constituents identify the hotspots in the binding interface of the structures.ConclusionEnergetic investigations of the four complexes suggest that many of the residues involved in the interactions are common. However, we found two receptor residues that were related to selective binding of the H3 and H4 ligands. Modifications or mutations on one of these residues can selectively alter the recognition of the H3 tails or the H4 tails.
Highlights
Histone methylation and demethylation have significant roles in transcriptional regulation and chromatin condensation [1]
Methylation of H3K4 is mostly associated with transcriptional activation, antagonizing the effect of the methylation of H3K9 and H3K36 whereas methylation of H4K20 is associated with gene silencing [15]
We have studied four complexes: JMJD2A-tudor domain structures bound to i) H3K4me3, ii) H4K20me3, iii) H4K20me2 and iv) H3K9me3
Summary
Histone methylation and demethylation have significant roles in transcriptional regulation and chromatin condensation [1]. Methylation of lysine residues in H3 and H4 histone proteins are involved in activation or repression of specific genes [2,3,4,5]. These histone proteins are one of the most slowly evolving proteins among all eukaryotic proteins and are extremely conserved [6] ( see [7] in all species). JMJD2A, recognizes and binds to methylated lysine residues at histone H3 and H4 tails (especially trimethylated H3K4 (H3K4me3), trimethylated H3K9 (H3K9me3) and di,trimethylated H4K20 (H4K20me, H4K20me3)) via its tandem tudor domains. Complete picture of the recognition of the four histone peptides by the tandem tudor domains yet remains to be clarified
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