Methylation Of Histone H3 Tail Lysine

Acetylation, methylation, phosphorylation, and ubiquitylation are distinct patterns of covalent histone modifications, all of which regulate DNA-based events in ways that were unimaginable a decade ago. Recently, histone lysine methylation has received much attention since more and more evidences have begun to emerge implicating failure of normal methylation of histone lysine in developmental disorders as well as in cancer. The thesis is about the theoretical calculations on the functional role of histone lysine methyltransferases, the effect of lysine methylation on cation-Ï€interaction and on interactions between histone H3 tail and effector protein, and the further influence of serine phosphorylation on interactions between methylated histone H3 tail and effector protein. The main contents as follows.(1) The transfer of methyl group(s) from the cofactor S-adenosyl methionine catalyzed by SET domain methyltransferases has been studied by means of ab intio and DFT calculations. The study shows that the enzymes can not yield special stabilization on the transition state; however, they provide a solvent-free room for the substrate and can bring the nucleophile and the electrophile together through the nearby residues in a perfect way, and therefore facilitate the methylation processes.(2) Each lysine can be either mono-, di-, or trimethylated. Different methylated lysine could be differentiated by effector protein through cation-Ï€interaction. Cation-Ï€interaction is the stabilizing force between a positive charge and the face of an aromatic ring in biological and chemical systems. The study focus on a series of computations on TMA-phenol system carried out with DFT and MP2 methods at level of 6-31+G**. The optimized structures obtained by the MP2 method are different from that obtained by the DFT method due to the influence of dispersion forces. Electron correlation contributes over 50% of total binding energy, and its influence on TMA-phenol system is similar to TMA-furan (50%) system, whereas much more significant than that in the TMA-imidzole (20%). Four different configurations for the TMA-phenol complex have been located. The interconverting barriers among the four binding models are less than 1 kcal/mol, significantly lower than those for the complex NH₄⁺-phenol. TMA cation interactions with aromatic systems are remarkably flexible with respect to orientation.(3) Drosophila HP1 is one of the effector proteins that contain the essential aromatic residues as the recognition pocket for trimethylated lysine histone H3 tail, not for nomethylated lysine histone H3 tail. 10-ns molecular dynamics simulations were used in this study to examine how the presence of monomethylated lysine 9 histone H3 tail compared with trimethylated lysine 9 H3 tail influenced the motions of the HP1 protein receptor and the interactions between H3 tail and HP1 protein. It's indicated that both the MeK and the surrounding histone tail sequence are necessary features of recognition which significantly affect the flexibility and backbone motions of HP1 chromodomain.(4) Different combinations of histone modifications at different residues may form a 'histone code' and act synergistically or antagonistically to affect gene expression. During mitosis in vivo, H3 lysine 9 methylation and serine 10 phosphorylation can occur concomitantly on the same histone tail. Serine 10 next to the trimethylated lysine 9 mark is phosphorylated by the kinase Aurora B, whereas the function of serine phosphorylation remains controversial. Molecular dynamics simulation of HP1 complexed with both trimethylated and phosphorylated H3 tail were performed and compared with the results from the methylated H3-HP1 trajectories. It is clear from the 10-ns dynamics simulation that two adjacent post-translational modifications directly increase the flexibility of the H3 tail and weaken HP1 binding to chromatin.The study described may provide useful information of histone lysine methylation. A combinatorial readout of two adjacent post-translational modifications—a stable methylation and a dynamic phosphorylation mark—establish a regulatory mechanism of protein-protein interactions in nature.