NLM IRP Seminar Schedule

Abstract:

Histone tails, representing the N-terminal or C-terminal disordered regions flanking the histone core, play critical roles in epigenetic regulation. However, little is known about the mechanisms of how histone tails modulate the nucleosomal and linker DNA solvent accessibility and recognition of nucleosomes by other macromolecules. Here, we generate extensive atomic level conformational ensembles of histone tails in the context of the full human nucleosome, totaling 65 microseconds of molecular dynamics simulations. We observe rapid conformational transitions between tail bound and unbound states, and characterize kinetic and thermodynamic properties of histone tail-DNA interactions. Our results show that different histone types exhibit distinct, although conformationally heterogeneous, binding modes and each histone type occludes specific DNA regions from the solvent. Using a comprehensive set of experimental nucleosome complex structures, we find that the majority of them target mutually exclusive regions with histone tails on nucleosomal/linker DNA around the super-helical locations?+/- 1, +/- 2, and +/- 7, and histone tails H3 and H4 contribute most to this process. These findings are explained within competitive binding and tail displacement models. Finally, we further investigate how histone tails' post-translational modifications (PTMs) and mutations alter tail dynamics and interactions, mediating binding of proteins to nucleosome.