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SIMULATION OF H2A.B CONTAINING HISTONE VARIANT NUCLEOSOME
Title
SIMULATION OF H2A.B CONTAINING HISTONE VARIANT NUCLEOSOME
Creator
Kohestani, Havva
Date
2019
Description
The H2A.B histone is a highly evolving vertebrate specific variant of the H2A histone family. It has been implicated in increased gene...
Show moreThe H2A.B histone is a highly evolving vertebrate specific variant of the H2A histone family. It has been implicated in increased gene expression, and experiments have shown that incorporation of H2A.B into nucleosomes results in more extended structures with fewer wrapped DNA base pairs. To study the molecular mechanisms of H2A.B, we have performed a series of conventional and enhanced sampling molecular dynamics simulation of H2A.B and canonical H2A containing nucleosomes.Results of adaptively biased molecular simulations show that substitution of canonical H2A with H2A.B results in geometrical changes such as unwrapping of 10 to 15 base pairs of DNA on each side of the nucleosome and an increase in the diameter and radius of gyration, which is in agreement with previous AFM, FRET, and SAXS experiments. DNA unwinding is energetically favorable in H2A.B containing compared to canonical nucleosomes, while in both systems we observe a wide range of sampling over various structures of DNA. H3 histone tails excluded simulations, show the importance and effect of N-terminal residues of H3 histones on attachment of DNA at the entry/exit sites to nucleosome protein core. Clustering and hydrogen bond analysis suggest that introduction of H2A.B to nucleosome systems triggers mechanisms leading to rearrangement of hydrogen bond network which may influence the pattern and intensity of interactions between DNA-protein and protein-protein complexes.
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STRUCTURE AND DYNAMICS OF MODIFIED NUCLEOSOMES UNDER EPIGENETIC REGULATION
Title
STRUCTURE AND DYNAMICS OF MODIFIED NUCLEOSOMES UNDER EPIGENETIC REGULATION
Creator
Kohestani, Havva
Date
2022
Description
Epigenetic regulations are critical in inducing heritable phenotype changes in biological systems without alternating their core genetic DNA...
Show moreEpigenetic regulations are critical in inducing heritable phenotype changes in biological systems without alternating their core genetic DNA sequences. In vivo, reversible epigenetic mechanisms engage various molecular structures from RNAs to larger proteins. The present thesis investigates the influence of epigenetic regulatory factors such as histone protein variants and small non-coding RNAs on the dynamics and structure of nucleosome core particles. Our results show that a histone substitution is an efficient tool in increasing or decreasing the exposure of DNA to post-translational modification (PTMs) factors or larger molecular assembly elements. Substitution of canonical H2A with H2A.B alters DNA-dimer interface resulting in increased breathing and accessibility of DNA. Replacement of canonical H3 with CENP-A variant impacts the overall core-DNA dynamics with flexibility of DNA entry/ exit sites and more rigid tetramer structure. Histone substitution also affects the micro to macro level molecular communication in the nucleosome system. The long-range correlated motions are weakened in H2A.B compared to canonical NCP. We observed a reduction in effective long-range DNA-DNA and DNA-core allosteric pathways in CENP-A NCP compared to canonical and Widom NCPs. Non-coding RNAs increase the tendency of the H3 tail histones to interact with DNA and induce the structural changes in the initial ideal B-DNA of NCP. Overall, the interaction of epigenetic regulatory factors in the form of protein or nucleic acids shifts the energetic and structural properties of the original nucleosome system. As a result, the chromatin structure is prepared to generate the proper biological response throughout spermatogenesis, chromosome segregation, or PTMs assembly.
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