Dynamics simulation on the flexibility and backbone motions of HP1 chromodomain bound to free and lysine 9‐methylated histone H3 tails

Abstract

ABSTRACT:Histone methylation has emerged as a central epigenetic modification with both activating and repressive roles in eukaryotic chromatin. Drosophila HP1 (heterochromatin-associated protein 1) is one of the chromodomain proteins that contain the essential aromatic residues as the recognition pocket for lysine methylated histone H3 tail. The aromatic cage indicates that the complex of chromodomain protein binding lysine methylated histone H3 tail can be seen as a typical host-guest system between protein and protein. About 10-ns molecular dynamics simulations have been carried out in this study to examine how the presence of mono-, trimethylated lysine 9 histone H3 tail (Me1K9, Me3K9 H3) influences the motions of HP1 protein receptor. The study shows that the conformation of HP1 protein free of H3 tail easily changes, whereas that of HP1 protein bound to methylated H3 tail does not. But the conformation of inserted Me1K9 H3 changes obviously as the Me1K recognition makes hydrogen-bonded interactions associated with the aromatic cage even more unstable than those in free HP1 protein. The conformational change of Me1K9 H3 is correlated with the motions of HP1 protein. As the recognition factor going from Me1K to Me3K produces a more favorable interaction for aromatic ring, hydrogen-bonded interactions associated with aromatic cage in Me3K9 H3-HP1 complex were observed to be much more stable than those in Me1K9 H3-HP1 complex and free HP1. Because of correlation, the flexibility of Me3K9 H3 decreases. The simulations indicate 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. These findings confirm a regulatory mechanism of protein-protein interactions through a trimethylated posttranslational modification.

Structural Role of RKS Motifs in Chromatin Interactions: A Molecular Dynamics Study of HP1 Bound to a Variably Modified Histone Tail

“…Several published macroscopic and CG-mesoscale models of chromatin (23)(24)(25)(26)(27)(28)(29)(30) were able to capture the relevant physicochemical features of DNA and nucleosomes, but, due to inherent limitations, could only approximate histone tails. The interactions and dynamics of modified and unmodified histone tails were recently studied by means of atomistic molecular dynamics (MD) simulations (31,32). A 10 ns MD simulation of HP1 in complex with the K9-trimethylated and S10phosphorylated H3 tail suggested that the two adjacent modifications increase the flexibility of the H3 tail and weaken HP1 binding to chromatin (33).…”

Mechanisms of histone lysine-modifying enzymes: A computational perspective on the role of the protein environment

“…mono-, di-or trimethylated lysines) of the histones. The influence of this cage in the recognition of different stated of methylation in lysine has been mainly studied by classical MD simulations, in a similar fashion to the bromodomain studies described above -most computational work has been performed for the chromodomains.Zhou[127] performed 10 ns molecular dynamics with the AMBER ff03 force field and TIP3P solvation to evaluate the flexibility of the Drosophila heterochromatin-associated protein 1 (HP1) in the free and histone H3 bound states. Zhou found that the free complex is much more flexible than with bound methylated histones.…”

Υπολογιστική Μελέτη Τροποποιημένων Ιστονών

“…Έλα απιφ παξάδεηγκα πνπ δειψλεη ηνπ ιφγνπ ην αιεζέο είλαη φηη κέρξη πξνζθάησο ε κεζπιίσζε ηεο ηζηφλεο εζεσξείην κία κε αληηζηξεπηή δηεξγαζία, φκσο πξφζθαηεο κειέηεο έδεημαλ ην αληίζεην[119]. Ο Y-K. Jiang θαη ε νκάδα ηνπ δεκνζίεπζαλ 2 εξγαζίεο ζηηο νπνίεο κειέηεζαλ ηελ δηακνξθσηηθή ζπκπεξηθνξά ηεο πξσηεΐλεο θαη ηνπ νιηγνπεπηηδίνπ κε πξνζνκνίσζε κνξηαθήο δπλακηθήο γηα ρξνληθφ δηάζηεκα 10 ns ζην ζχζηεκα ηεο HP1 κε ηελ H3[120,121]. πγθεθξηκέλα έγηλαλ κειέηεο ζε κνλν-θαη ηξηκεζπιησκέλα θαηάινηπα ηεο ιπζίλεο 9 ηεο ηζηφλεο H3 φηαλ βξίζθεηαη καδί κε ηελ HP1.…”