Biophysical Society Thematic Meeting| Les Houches 2019

Multiscale Modeling of Chromatin: Bridging Experiment with Theory

Poster Abstracts

26-POS Board 26 A METADYNAMICS APPROACH FOR THE MODELLING OF INTRINSICALLY DISORDERED CHROMATIN BINDING PROTEINS Akshay Sridhar 1 ; Rosana Collepardo-Guevara 1 ; 1 University of Cambridge, Maxwell Centre, Cavendish Laboratory, Cambridge, Cambridgeshire, United Kingdom DNA in-vivo is complexed with histone proteins to form chromatin - an array of nucleosomes separated by linker DNA. While enabling considerable condensation of DNA, chromatin also allows additional complexity above the genetic code as its structure is intimately linked to gene expression. A range of chromatin-binding proteins participate in the remodelling and maintenance of chromatin structure. However, the high-resolution modelling of these chromatin- binding proteins is often hindered by them being particularly enriched in Intrinsically Disordered Regions (IDR) - regions with structural diversity and high flexibility. Through two protein test cases - H1 and HP1, we demonstrate the applicability of Metadynamics simulations to improve sampling and thereby aid in discerning the structural mechanisms of functioning of such chromatin binding IDRs. H1 Linker Histones (LH) are composed of a structured globular domain and unstructured terminal domains. However, structural studies of H1-nucleosome binding have been limited to the globular domain. Through a metadynamics setup that biases the IDP’s secondary structure and its interactions with DNA, we demonstrate that the long unstructured C-terminal domain bridges DNA through flexible loops. Additionally, we show the shorter unstructured N-terminal domain to contribute to the differential binding of H1 subtypes through differences in their amphiphilic helical conformations. Heterochromatin Protein 1 (HP1) binds to the H3 tails of nucleosomes and plays an important role in gene regulation and the formation of Heterochromatin. The protein consists of intrinsically disordered terminals together with a disordered central hinge region that bridges two structured domains. These disordered regions are hypothesised to enable the functioning of HP1 through a multitude of intra- and inter-molecular contacts. Using metadynamics simulations, we determine conformations of the unstructured N-terminal domain and the associated changes upon its Phosphorylation that enable HP1’s binding to the nucleosomal H3 tails.

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