Computational Modelling of Histone Deacetylases 5

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Every cells in the body goes through a cell cycle phase where they need to grow, proliferate, differentiate and die. Any alteration in the cell cycle can lead into Cancer. Cancer is a condition were the cells grow at an uncontrolled rate. The cancerous cells can invade and destroy surrounding healthy cells, tissues and also organs. It has been realised that Histones play an important role in cancer development.

Histones are the most abundant proteins associated with the eukaryotic DNA. Eukaryotic cells contain histones. These histones are of five types viz. H2A, H2B, H3, H4 and H1, from which the H1 is the linker histone and H2A, H2B, H3 and H4 are core histones. A pair of these core histones assemble to form an octamer. To this octamer, the DNA is wrapped and hence this assembly is known as “nucleosome”. The remaining linker histone is associated with the nucleosome for maintaining the chromosome structure. When histones are isolated from cells, their Nterminal tails are modified with small molecules. Lysines are acetylated or methylated while serines are phosphorylated. These histone modifications are mediated by specific enzymes. Histone acetyl transferases (HATs) are responsible for acetylation of the lysines while histone deacetylases (HDACs) removes these modifications. Due to their critical role in regulation of chromatin structure and gene expression, HDACs have become major drug targets. HDAC inhibitors are specific toward tumour cells. This is the reason why they are used as anticancer drugs.2-4

Histone deacetylases are class of enzymes which act inremoval of acetyl groups from a ϵ-N-acetyl lysine amino acid on a histone, because of which the DNA is wrapped around the histones tightly. There are in all 4 classes in which all 18 Histone deacetylases are classified. Class I comprises of HDAC-1, HDAC-2, HDAC-3 and HDAC-8. Class II is divided into two sub-classes – Class IIA and Class IIB in which Class IIA comprises of HDAC-4, HDAC-5, HDAC-7 and HDAC-9 and Class IIB comprises of HDAC-6 and HDAC-10. Class III are known as Zn-dependent histone deacetylases, comprising of zinc. Class IV comprises of the

remaining HDAC-11.          

HDAC-5 is a protein coding gene. It is located on 17q21. Diseases associated with HDAC-5 include intellectual

disability, herpes simplex and various types of cancers. The main role of HDAC-5 is deacetylation of lysine

residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). It also plays an important role in

transcriptional regulation, histone deacetylation which gives a tag for epigenetic repression, cell cycle progression and developmental events.


Currently, there is no published 3D structure model available for HDAC-5 (Q9UQL6). As a result, we planned a

study where we are going to build a 3D structure for HDAC-5 with the help of suitable bioinformatics tools. The

modelled HDAC-5 can be further used for docking studies in development of novel HDAC inhibitor molecules.



The 3D structure of HDAC-5 (Q9UQL6) is unavailable in Uniprot under Protein Knowledgebase (UniProtKB). Its FASTA Sequence of HDAC-5 was retrieved from UniProtKB Database and then subjected to physiochemical and

functional characterization. I-TASSER was used to build the model and the best model was selected on the basis of confidence score. The refinement of the model was done by using Swiss-Pdb Viewer and later on validation of

the model was done by RAMPAGE Server. The FASTA Sequence which was used is mentioned below-


Physiochemical Characterization

The information of HDAC-5 regarding its molecular weight, theoretical isoelectric point, instability index, aliphatic index, GRAVY, atomic composition, amino acid composition and extinction coefficient are all included in physiochemical characterization. For retrieving information of physiochemical characterization, Expasy Protparam Server was used. The result is presented in Table 1. Table 3 highlights the Amino Acid Composition of HDAC-5.

Functional Characterization

For prediction of transmembrane helices and topology of proteins, HMMTOP Server has been used and Cys_Rec is used for Predicting SS-bonding States of Cysteines and disulphide briges in Protein Sequences. The result of Cys_Rec is presented in Table 2.


Model Building& Refinement

The 3D structure of HDAC-5 was modelled using I-TASSER. The top 10 templates which are shown in Table 4 were

used to build the model by I-TASSER. The I-TASSER Results are presented in Table 5.

Confidence Score (C-score)

should be in the range of [-5 to 2], where a C-score of higher value signifies a model with a high confidence and

vice versa. With the help of the C-score, the best among the resultant modelled structure was selected. The

Energy Minimization of the modelled HDAC-5 was done using Swiss-Pdb Viewer. Figure 1 shows the Energy Minimised Model of HDAC-5 using UCSF Chimera.11


Model Refinement & Validation

Energy Minimization of the 3D structure was done using Swiss-Pdb Viewer. HDAC-5 has Torsion of 7540.591,

Electrostatic Energy -25198.29 KJ/mol and total energy - 15077.916 KJ/mol. Figure 1 shows the refined structure of HDAC-5 using UCSF Chimera.


The 3D model was validated by RAMPAGE Server by verifying the parameter of Ramachandran Plot quality (Figure2). The Plot Analysis are presented in Table 6.



This study presents the methodology for generating 3D structure models for proteins whose crystal structures are

not available. A computational model of HDAC-5 was successfully designed by combining the primary sequence

studies, secondary structure analysis, molecular modelling and validation approaches. This 3D model of

HDAC-5 can further be used for various drug discovery studies.

Posted by: Akshay S Jadhav. in Science | Date: 03/03/2016

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