Date of Award

Spring 5-15-2022

Degree Type


Degree Name

Doctor of Philosophy (PhD)


Biomedical and Chemical Engineering


Nangia, Shikha

Subject Categories

Biomedical Engineering and Bioengineering | Engineering


Epigenetics is a growing area of research that could potentially unlock the understanding of questions like how and why we develop certain diseases, how we age, how we inherit certain traits and even how our species evolves. Epi is a prefix meaning above, referring to chemical tags that sit above your genetics and dictate gene expression. Although there are many known links between certain epigenetic tags and diseases like cancer, the molecular mechanisms behind these links remains elusive. Gaining a novel understanding of the behavior of key biological targets for cancer like the histone H3 tail motivated this work. Histone tails are integral structural and functional components of the eukaryotic nucleosome. These tails, rich in positively charged amino acid residues, interact with the DNA to stabilize the nucleosomal structure. However, capturing the biochemical effects of posttranslational modifications (PTMs) on histone tails in molecular detail using X-ray or NMR techniques remains a challenge due to their intrinsically disordered structure. In this work, we studied the N-terminal portion of the H3 histone protein, a 38-residue tail, that when posttranslationally modified, is implicated in altering the tail's interaction with the DNA, affecting nucleosomal stability. Using all-atom molecular dynamics simulations for a total of 35 microseconds, we investigated the structure and dynamics of the wildtype H3 tail and seven known nucleosomal PTMs. Based on residues' contacts with DNA, water, and ions, dihedral angle analysis, and root-mean-square fluctuations of the tail residues, our results show that the H3 tail has a tripartite segmental nature. The three segments, labeled I, II, and III, are separated by the proline residues P16, P30, and P38. A comparison of wildtype H3 tail and proline-to-alanine-mutated H3 tail showed that the prolines function as segmental dividers or hinges of the H3 tail. We show that Segment I is more dynamic than Segments II and III, and Segment I makes multiple transient contacts with the DNA. The PTMs affect the tail'sII dynamics to different extents, but the tripartite segmental nature of the tail is preserved. Notably, single-residue modification of the lysine by acetylation or methylations in Segment I versus multiple residue modifications by serine phosphorylation or lysine methylations have marked effects on the tail's flexibility and interaction with the DNA. This study highlights the significance of proline residues in creating the segmental behavior of the H3 tail. Chapters 3 and Chapters 4 profile the same computational methods utilized in Chapter 2 on other biological systems. Each presents its own learnings and were foundational to the authors understanding of post translational modifications and molecular simulations.


Open Access