Metillenmiş histon peptitlerinin JMJD2A enziminin bitişik tudor domenleri tarafından moleküler düzeyde tanınmaları

In this thesis, we report a detailed molecular dynamics simulation and MM-PBSA/GBSA approach (MM: Molecular Mechanics; PB: Poisson Boltzmann; GB: Generalized Born; SA: Surface Area) analysis, unraveling the recognition of the methylated histone tails H3K4me3, H4K20me3, H4K20me2 and H3K9me3 by JMJD2A-tudor. In this respect, 25 ns fully unrestrained molecular dynamics simulations were conducted for each of the bound and free structures. We investigated the important hydrogen bonds and coulombic interactions between the tudor domains and the peptide molecules; hence unveiled critical residues occupied in stabilizing the complexes. Normal mode and molecular mechanics calculations were performed to obtain the entropic determinants of the binding affinities. Suggested by the resulting binding free energies obtained via GB and PB approaches, we found that H4K20me3 peptide has the highest affinity to JMJD2A-tudor in GB calculations whereas H4K20me2 peptide has the highest affinity to JMJD2A-tudor in PB calculations. Furthermore, we discerned that H3K9me3 peptide has the lowest affinity to JMJD2A-tudor in both of the model calculations. We also revealed that while H4K20me2 peptide adopting the same binding mode with H4K20me3 peptide, H3K9me3 peptide adopts the same binding mode with H3K4me3 peptide. Decomposition of the enthalpic and the entropic contributions to the binding free energies indicated that the recognition of the histone peptides is mainly driven by favourable van der Waals interactions in both GB and PB models. Based on GB calculations pairwise and per residue decomposition of the binding free energies with backbone and sidechain contributions as well as their energetic constituents were also carried out to identify the hotspots of the structures. Thus, the van der Waals and the electrostatic interactions which are prominent for the recognition of the peptides were clarified.