Abstract
Polycomb group (PcG) proteins have been observed to maintain the pattern of histone by methylation of the histone tail responsible for the gene expression in various cellular processes, of which enhancer of zeste homolog 2 (EZH2) acts as tumor suppressor. Overexpression of EZH2 results in hyper activation found in a variety of cancer. Point mutation on two important residues were induced and the results were compared between the wild type and mutant EZH2. The mutation of Y641 and A677 present in the active region of the protein alters the interaction of the top ranked compound with the newly modeled binding groove of the SET domain, giving a GLIDE score of −12.26 kcal/mol, better than that of the wild type at −11.664 kcal/mol. In depth analysis were carried out for understanding the underlying molecular mechanism using techniques viz. molecular dynamics, principal component analysis, residue interaction network and free energy landscape analysis, which showed that the mutated residues changed the overall conformation of the system along with the residue-residue interaction network. The insight from this study could be of great relevance while designing new compounds for EZH2 enzyme inhibition and the effect of mutation on the overall binding mechanism of the system.
Highlights
Literature survey shows that the active region of the structure of Enhancer of zeste homolog protein 2 (EZH2) enzyme, which is present in the SET domain, does not display ligand docking despite efforts being made in order to crystallize the structure in the presence of cofactors and inhibitors[7]
A CXC domain was observed in the C-terminal region of EZH2 along with catalytic I-SET, SET, and post-SET domains
The residues in the active site of the SET domain were partially missing and the EZH2 PDB model was considered unsuitable for further molecular docking studies leading to the remodeling of the protein
Summary
By isolating these natural compounds, it may be possible to come up with more potent drugs which can further be manipulated so as to make it more efficient and safe for humans. Literature survey shows that the active region of the structure of EZH2 enzyme, which is present in the SET domain, does not display ligand docking despite efforts being made in order to crystallize the structure in the presence of cofactors and inhibitors[7]. This can be solved by remodeling the active site region of the enzyme by selecting the best homologous structure available. Insights to the effect of mutation on the mechanism of binding can be further understood, giving a clear overview of all the underlying process on a molecular level
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