Molecular Recognition of H3/H4 Histone Tails by the Tudor Domains of JMJD2A: A Comparative Molecular Dynamics Simulations Study

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.

[1]  Wei Zhang,et al.  A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculations , 2003, J. Comput. Chem..

[2]  M. Sattler,et al.  Tudor hooks up with DNA repair , 2007, Nature Structural &Molecular Biology.

[3]  T. Darden,et al.  A smooth particle mesh Ewald method , 1995 .

[4]  Patricia A. Ortiz-Tello,et al.  Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase , 2007, Nature Structural &Molecular Biology.

[5]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[6]  Jing-Fei Huang,et al.  Discovery Studio 2.0的模块扩展及应用：残基水平非键相互作用能量的自动批量计算 , 2011 .

[7]  Holger Gohlke,et al.  Converging free energy estimates: MM‐PB(GB)SA studies on the protein–protein complex Ras–Raf , 2004, J. Comput. Chem..

[8]  Benjamin J. Hsu,et al.  The histone database: A comprehensive resource for histones and histone fold‐containing proteins , 2005, Proteins.

[9]  Ozlem Keskin,et al.  Restricted mobility of conserved residues in protein-protein interfaces in molecular simulations. , 2008, Biophysical journal.

[10]  Yang Shi,et al.  Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1 , 2004, Cell.

[11]  Georges Mer,et al.  Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor , 2008, Nature Structural &Molecular Biology.

[12]  R. Janknecht,et al.  Diversity within the JMJD2 histone demethylase family. , 2007, Biochemical and biophysical research communications.

[13]  P. Kollman,et al.  Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models , 1992 .

[14]  Laxmikant V. Kale,et al.  NAMD2: Greater Scalability for Parallel Molecular Dynamics , 1999 .

[15]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998, J. Comput. Chem..

[16]  Jon R. Wilson.  Targeting the JMJD2A histone lysine demethylase , 2007, Nature Structural &Molecular Biology.

[17]  Ozlem Keskin,et al.  Architectures and functional coverage of protein-protein interfaces. , 2008, Journal of molecular biology.

[18]  S. Wu,et al.  The JMJD2 members of histone demethylase revisited , 2008, Molecular Biology Reports.

[19]  R. Yeh,et al.  Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells , 2008, Oncogene.

[20]  A. Bogan,et al.  Anatomy of hot spots in protein interfaces. , 1998, Journal of molecular biology.

[21]  Ozlem Keskin,et al.  Analysis of Hot Region Organization in Hub Proteins , 2010, Annals of Biomedical Engineering.

[22]  D. Case,et al.  Exploring protein native states and large‐scale conformational changes with a modified generalized born model , 2004, Proteins.

[23]  David S. Goodsell,et al.  A semiempirical free energy force field with charge‐based desolvation , 2007, J. Comput. Chem..

[24]  Aytug Tuncel,et al.  Investigation of the Interaction between the Large and Small Subunits of Potato ADP-Glucose Pyrophosphorylase , 2009, PLoS Comput. Biol..

[25]  P. Grant,et al.  The generation and recognition of histone methylation. , 2006, Results and problems in cell differentiation.

[26]  Jörg Weiser,et al.  Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO) , 1999, J. Comput. Chem..

[27]  Yang Shi,et al.  Structural basis of the recognition of a methylated histone tail by JMJD2A , 2007, Proceedings of the National Academy of Sciences.

[28]  B. Brooks,et al.  Constant pressure molecular dynamics simulation: The Langevin piston method , 1995 .

[29]  K. Sharp,et al.  Accurate Calculation of Hydration Free Energies Using Macroscopic Solvent Models , 1994 .

[30]  T. Kundu,et al.  Chromatin and Disease , 2007 .

[31]  R. Schüle,et al.  The expanding world of histone lysine demethylases , 2007, Nature Structural &Molecular Biology.

[32]  Johann Gasteiger,et al.  A new model for calculating atomic charges in molecules , 1978 .

[33]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[34]  M. L. Connolly.  Analytical molecular surface calculation , 1983 .

[35]  X. de la Cruz,et al.  Do protein motifs read the histone code? , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[36]  Ozlem Keskin,et al.  HotPoint: hot spot prediction server for protein interfaces , 2010, Nucleic Acids Res..

[37]  Manuel C. Peitsch,et al.  SWISS-MODEL: an automated protein homology-modeling server , 2003, Nucleic Acids Res..

[38]  W. C. Still,et al.  Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO) , 1999 .

[39]  Yi Zhang,et al.  Recognition of Histone H3 Lysine-4 Methylation by the Double Tudor Domain of JMJD2A , 2006, Science.

[40]  M F Sanner,et al.  Python: a programming language for software integration and development. , 1999, Journal of molecular graphics & modelling.

[41]  Emil Alexov,et al.  Rapid grid‐based construction of the molecular surface and the use of induced surface charge to calculate reaction field energies: Applications to the molecular systems and geometric objects , 2002, J. Comput. Chem..

[42]  Antoine H. F. M. Peters,et al.  LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription , 2005, Nature.

[43]  M. Klein,et al.  Constant pressure molecular dynamics algorithms , 1994 .

[44]  Steven Henikoff,et al.  Phylogenomics of the nucleosome , 2003, Nature Structural Biology.

[45]  Ozlem Keskin,et al.  Identification of computational hot spots in protein interfaces: combining solvent accessibility and inter-residue potentials improves the accuracy , 2009, Bioinform..

[46]  Ozlem Keskin,et al.  Insights into subunit interactions in the heterotetrameric structure of potato ADP-glucose pyrophosphorylase. , 2008, Biophysical journal.

[47]  D. Case,et al.  Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. , 2003, Journal of molecular biology.