Ligand release mechanisms and channels in histone deacetylases

Exploring the molecular channels of class I histone deacetylases (HDACs) with buried active sites are important to understand their structures and functionalities. In this work, we perform hybrid classical molecular dynamics and random acceleration molecular dynamics simulations to explore the B3N [i.e., (4‐(dimethylamino)N‐[7(hydroxyamino)‐7‐oxoheptyle] benzamide)] exit channels in the x‐ray crystal structures of HDAC3 and HDAC8 enzymes. Our simulations identify B3N release through four different channels in HDAC3 (denoted as A1, A2, B1, and B2) and HDAC8 (referred as A1, B1, B2, and B3) enzymes, among which egression through channel A1 is more predominant in both the enzymes. This mechanism is similar to ligand release in HDAC1 and HDAC2 described in our previous study and can be the fingerprint ligand release mechanisms in class I HDACs. Ligand release events through B channels, on the other hand, are different among HDAC3 and HDAC8, highlighting the significances of substituted residues in controlling the access to these channels This study reveals a novel aromatic gating mechanism elicited by TYR154‐TRP141‐TYR111 that controls the B3N access to all the B channels in HDAC8. The TRP141 in HDAC8 is substituted by LEU133 in HDAC3, which do not hinder the access to B channels in HDAC3. However, two hydrogen bonded barricades formed as ARG28‐GLY297‐GLY295‐GLY131 and TRP129‐ARG28‐ALA130‐LEU29‐TRP129 obstruct the B3N from exploring the B channels in HDAC3. The structural and dynamical characterizations of molecular channels and ligand unbinding mechanisms reported in this study provide novel structural insights and atomic level perspectives on HDAC3 and HDAC8 enzymes, thereby potentially aiding in the design of more specific HDAC inhibitors.Copyright © 2013 Wiley Periodicals, Inc.

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

[2]  C. Fierke,et al.  On the function of the internal cavity of histone deacetylase protein 8: R37 is a crucial residue for catalysis. , 2011, Bioorganic & medicinal chemistry letters.

[3]  M. Salto‐Tellez,et al.  Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1 , 2005, Cell Death and Differentiation.

[4]  Rebecca C Wade,et al.  The ins and outs of cytochrome P450s. , 2007, Biochimica et biophysica acta.

[5]  Lennart Nilsson,et al.  Unbinding of retinoic acid from the retinoic acid receptor by random expulsion molecular dynamics. , 2006, Biophysical journal.

[6]  P. Marks,et al.  Histone Deacetylase Inhibitors: Overview and Perspectives , 2007, Molecular Cancer Research.

[7]  Amos Bairoch,et al.  Swiss-Prot: Juggling between evolution and stability , 2004, Briefings Bioinform..

[8]  R. Wade,et al.  How do substrates enter and products exit the buried active site of cytochrome P450cam? 1. Random expulsion molecular dynamics investigation of ligand access channels and mechanisms. , 2000, Journal of molecular biology.

[9]  Yi-Ping Phoebe Chen,et al.  Structure-based drug design to augment hit discovery. , 2011, Drug discovery today.

[10]  Matthieu Schapira,et al.  Structural biology of human metal-dependent histone deacetylases. , 2011, Handbook of experimental pharmacology.

[11]  Silvio Massa,et al.  Histone deacetylation in epigenetics: An attractive target for anticancer therapy , 2005, Medicinal research reviews.

[12]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[13]  Masaaki Kawata,et al.  Particle mesh Ewald method for three-dimensional systems with two-dimensional periodicity , 2001 .

[14]  A. Laio,et al.  Metadynamics: a method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science , 2008 .

[15]  G. Estiu,et al.  Residues in the 11 A channel of histone deacetylase 1 promote catalytic activity: implications for designing isoform-selective histone deacetylase inhibitors. , 2008, Journal of medicinal chemistry.

[16]  Michael Bots,et al.  Rational Combinations Using HDAC Inhibitors , 2009, Clinical Cancer Research.

[17]  Francesco Pietra,et al.  Molecular‐Dynamics Simulation of Dioxygen Egress from 12/15‐LipoxygenaseArachidonic Acid Complex , 2012, Chemistry & biodiversity.

[18]  P. Atadja,et al.  Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors. , 2011, Bioorganic & medicinal chemistry.

[19]  Christopher B. Harrison,et al.  Structural origin of selectivity in class II-selective histone deacetylase inhibitors. , 2008, Journal of medicinal chemistry.

[20]  Yong Duan,et al.  Chromophore channeling in the G-protein coupled receptor rhodopsin. , 2007, Journal of the American Chemical Society.

[21]  Subha Kalyaanamoorthy,et al.  Energy based pharmacophore mapping of HDAC inhibitors against class I HDAC enzymes. , 2013, Biochimica et biophysica acta.

[22]  Yi-Ping Phoebe Chen,et al.  Exploring Inhibitor Release Pathways in Histone Deacetylases Using Random Acceleration Molecular Dynamics Simulations , 2012, J. Chem. Inf. Model..

[23]  Y. Duan,et al.  Ligand entry and exit pathways in the beta2-adrenergic receptor. , 2009, Journal of molecular biology.

[24]  Dong Long,et al.  Molecular Dynamics Simulation of Ligand Dissociation from Liver Fatty Acid Binding Protein , 2009, PloS one.

[25]  Feng Chen,et al.  Identifying targets for drug discovery using bioinformatics , 2008 .

[26]  VINCENT ZOETE,et al.  SwissParam: A fast force field generation tool for small organic molecules , 2011, J. Comput. Chem..

[27]  M. Jung,et al.  Inhibitors of histone deacetylase as new anticancer agents. , 2001, Current medicinal chemistry.

[28]  Feng Chen,et al.  Using bioinformatics techniques for gene identification in drug discovery and development. , 2008, Current drug metabolism.

[29]  Guang Ping Cao,et al.  Classification of HDAC8 Inhibitors and Non-Inhibitors Using Support Vector Machines , 2012 .

[30]  J. Schwabe,et al.  Structure of HDAC3 bound to corepressor and inositol tetraphosphate , 2011, Nature.

[31]  J. R. Somoza,et al.  Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. , 2004, Structure.

[32]  M. Dokmanovic,et al.  Prospects: Histone deacetylase inhibitors , 2005, Journal of cellular biochemistry.

[33]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[34]  E. Seto,et al.  Negative Regulation of Histone Deacetylase 8 Activity by Cyclic AMP-Dependent Protein Kinase A , 2004, Molecular and Cellular Biology.

[35]  A. Cavalli,et al.  Single-molecule pulling simulations can discern active from inactive enzyme inhibitors. , 2010, Journal of the American Chemical Society.

[36]  C. Abrams,et al.  Ligand escape pathways and (un)binding free energy calculations for the hexameric insulin-phenol complex. , 2008, Biophysical journal.

[37]  Guang Song,et al.  Efficient mapping of ligand migration channel networks in dynamic proteins , 2011, Proteins.

[38]  A. V. van Kuilenburg,et al.  Histone deacetylases (HDACs): characterization of the classical HDAC family. , 2003, The Biochemical journal.

[39]  M. Lübbert,et al.  Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy , 2010, Clinical Epigenetics.

[40]  O. Wiest,et al.  On the function of the 14 A long internal cavity of histone deacetylase-like protein: implications for the design of histone deacetylase inhibitors. , 2004, Journal of medicinal chemistry.

[41]  Ting Wang,et al.  Retinal release from opsin in molecular dynamics simulations , 2011, Journal of molecular recognition : JMR.

[42]  James D. Winkler,et al.  Cloning and Characterization of a Novel Human Class I Histone Deacetylase That Functions as a Transcription Repressor* , 2000, The Journal of Biological Chemistry.

[43]  R. De Francesco,et al.  Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex , 2007, EMBO reports.

[44]  Zbynek Prokop,et al.  Pathways and mechanisms for product release in the engineered haloalkane dehalogenases explored using classical and random acceleration molecular dynamics simulations. , 2009, Journal of molecular biology.

[45]  Yuji Nagata,et al.  Redesigning dehalogenase access tunnels as a strategy for degrading an anthropogenic substrate. , 2009, Nature chemical biology.

[46]  P. Marks,et al.  Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors , 1999, Nature.

[47]  E. Seto,et al.  Histone deacetylases : the biology and clinical implication , 2011 .

[48]  M. Navre,et al.  Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides. , 2010, Bioorganic & medicinal chemistry letters.

[49]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[50]  J. Bradner,et al.  On the inhibition of histone deacetylase 8. , 2010, Bioorganic & medicinal chemistry.

[51]  K. Schulten,et al.  Molecular dynamics study of unbinding of the avidin-biotin complex. , 1997, Biophysical journal.

[52]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[53]  Haishan Wang,et al.  New patented histone deacetylase inhibitors , 2009, Expert opinion on therapeutic patents.