JMJD2A enziminin metilasyon spesifisitesinin karşılaştırmalı moleküler dinamik çalışması

Specific patterns of post-translational modifications of histones act as a molecular ?code? recognized and used by non-histone proteins to regulate specific chromatin functions. K9 methylation on Histone 3 (H3) tail, mainly trimethylation, induces formation of constitutive heterochromatin via a well-known pathway, which employs heterochromatin formation protein (HP1) and DNA methyl transferase (DNMT). Jumonji domain containing 2A (JMJD2A) is a histone demethylase that specifically removes K9 and K36 trimethyl marks on H3 tail. This enzyme does not function on monomethyl marks and has almost 20-fold reduced activity on dimethyl forms compared to trimethyl forms.In order to gain insight into how JMJD2A discriminates between its substrates, we performed molecular dynamics simulations of mono-, di- and trimethylated histone tails in complex with JMJD2A catalytic domain and analyzed positional fluctuations, located the hydrogen bonds and calculated some critical distances. We revealed the importance of water molecules and the oxygen-enclosed environment in appropriate orientation of methylammonium head in the active site. We also calculated binding free energy and energy contribution of each residue. We found out that recognition is mostly driven by van der Waals and Coulombic interactions in enzyme-substrate interface. We also revealed the role of Arg8 on the H3 tail in binding and stabilizing the necessary conformation of substrate peptide.