Molecular recognition of H3/H4 histone tails by the tudor domains of JMJD2A: a comparative molecular dynamics simulations study

Abstract

Background: Histone 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 findings: We 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.

Conclusion: Energetic 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.

Figure 1. Secondary structure of JMJD2A-tudor domains.

The tandem hybrid tudor domains have an interdigitated structure in which structural motifs are exchanged between each other. β2 and β3 strands are swapped between the hybrid domains. The two lobes of the structure are named as Hybrid tudor Domain 1 (HTD-1) and Hybrid tudor Domain 2 (HTD-2).

Figure 2. Motion between the tandem hybrid tudor domains of JMJD2A.

The arrows show the direction of opening/closing motion. Different colours indicate the conformations of different snapshots during the simulations.

Figure 3. Two different binding modes of JMJD2A-tudor (A) with liganded to H3K4me3 (red) and H3K9me3 (yellow) (B) with liganded to H4K20me3 (cyan) and H4K20me2 (magenta).

First two peptides bind to the HTD-2 with a similar mode in the same orientation, whereas the later peptides bind in the opposite orientation with a similar mode.

Figure 4. Dihedral angles of the methylated lysine residue defined by C_δ, C_ε, N_ζ and CZ atoms in the JMJD2A-tudor molecule liganded to H3K4me3 (A), H4K20me3 (B), H4K20me2 (C) and H3K9me3 (D), respectively.

Figure 5. Activation potential energies between conformational states of the methylated lysine residues of H3K4me3 (A), H4K20me3 (B), H4K20me2 (C) and H3K9me3 (D) peptides.

Gauche⁺, gauche⁻ and trans conformations were shown as g⁺, g⁻ and t respectively. Energy values are in kcal/mol units and a temperature dependant c constant was removed from each of the energy values.

Figure 6. Detailed views of the residues that are involved in forming hydrogen bonds and salt bridges in the tudor domains liganded to H3K4me3 (A), H4K20me3 (B), H4K20me2 (C) and H3K9me3 (D) structures.

Hydrogen bonds are represented in blue dashed lines.

Figure 7. Molecular surface representation of JMJD2A-tudor.

The hotspot residues in the receptor are shown with red colour. Shown in licorice representation with cyan colour, the ligand residues of H3K4me3 (A), H4K20me3 (B), H4K20me2 (C) and H3K9me3 (D) structures are represented in the figure.

Figure 8. Snapshots of the MD simulations showing the hotspot residues of JMJD2A-tudor complexed with H3K4me3 (A), H4K20me3 (B), H4K20me2(C) and H3K9me3 (D) peptides.