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Intrinsically Disordered Proteins within the Genome



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Sridhar, Akshay 


The hundreds of millions of DNA base pairs within eukaryotic cells are not found free but packed inside the micrometre-sized nuclei through the formation of a macromolecular structure known as chromatin. Chromatin consists of a chain of nucleosomes – nucleoprotein complexes where the DNA makes ∼1.75 turns around a protein octamer core composed of two copies each of H2A, H2B, H3 and H4 histones. A fifth histone H1 binds on the nucleosomal surface close to the entry/exit site of DNA, interacts with linker DNA and aids in chromatin compaction. Enabling the condensation of DNA to fit into the nucleus is however only one-half of chromatin’s role. The three-dimensional spatial organization of chromatin serves a second important role in allowing the capability to exert control over gene expression. The chromatin structure thus serves as an additional layer of complexity above the genome code and permits the transcription of different proteins varying with cell lineages/cycles.

The proteins that makeup, modify and read the chromatin structure are particularly enriched in Intrinsic Disorder’ – a class of proteins lacking a well-defined structure but existing as a dynamic ensemble of rapidly interchanging states. While folded proteins with well-defined structures are amenable to be characterized through standard methods of protein structure determination, the plasticity’ of the disordered proteins challenges the use of such ensemble averaged techniques. In this thesis, Molecular Dynamics simulations are used to characterize the disordered regions of three proteins that form the core of chromatin structure: histones, linker histones (H1) and heterochromatin protein (HP1). The carboxy-terminal domain of H1 when within the nucleosome, adopts a compact but unstructured conformation that allows its positioning between the two linker DNA strands. In contrast, the amino-terminal domain of H1 undergoes a disorder-to-order transition to an amphiphilic helical conformation. The transition to the amphiphilic helix is however subtype-dependant with the degree of condensation varying with the subtypes' nucleosomal affinity. Finally, the simulations demonstrate that the affinity of HP1 subtypes for the H3 histone is caused by the synergetic effects of both the proteins' unstructured amino-terminal domain and the structured chromodomain.





Collepardo-Guevara, Rosana


Chromatin, Histones, Intrinsically Disordered Protein, Molecular Dynamics, Enhanced Sampling Simulations, Metadynamics, Linker Histone, Nucleosome


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge