UNCOVERING BIOPHYSICAL PROPERTIES AND FUNCTIONS OF DISORDERED HISTONES USING COMPUTER SIMULATIONS
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It is a crucial task for the continuation of every species to safely store genetic information and precisely pass it on to the next generation. For all the eukaryotes including humans, this mission is carried out by chromatin, a polymer chain consisting of repeating structural units called the nucleosome, in which 146 bp of DNA wraps around a histone protein octamer. In a typical eukaryotic cell, about two meters of DNA is compacted into a micrometer-sized nucleus, where transcription and replication activities are regulated in part via modulating chromatin's condensation. A comprehensive understanding of chromatin structure and dynamics provides the necessary foundation for explaining the genome organization, which, for example, will help better understand the mechanisms of diseases caused by epigenetic modifications. As the building blocks of chromatin and nucleosome, the histone proteins are the key players in chromatin structure regulation and epigenetic control. However, studying histones has been challenging in part because histone tails lack well-defined structures, staying disordered when carrying out many functions. In this dissertation, we focus on exploring the biophysical mechanisms related to these intrinsically disordered histones using computer simulations, carefully comparing our results with related experiments. We present recent progress in the development and applications of state-of-art molecular dynamics force fields for disordered histones and histone-DNA interactions. We used these force fields to investigate the structural, dynamical, and thermodynamical properties of various disordered histones, including histone tails, linker histones, and histone monomers, in the nucleosomal environment. Our investigations have uncovered the structural preferences and binding/folding dynamics of these disordered histones, which provide novel insights into how they aid chromatin condensation.