Chemistry & Biochemistry
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Item EPIGENETICS TUNE CHROMATIN MECHANICS, A COMPUTATIONAL APPROACH(2021) Pitman, Mary; Papoian, Garegin A; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The base unit of DNA packaging in eukaryotes, the nucleosome, is adaptively modified for epigenetic control. Given the vast chemical space of chromatin and complexity of signaling and expression, much of our knowledge about genetic regulation comes from a biochemical or structural perspective. However, the architecture and function of chromatin also mechanically responds to non-equilibrium forces. Mechanical and biochemical properties are not independent of one another and the interplay of both of these material properties is an area of chromatin physics with many remaining questions. Therefore, I set out to determine how the material properties of chromatin are altered by biochemical variations of nucleosomes. All-atom molecular dynamics is employed coupled with new computational and theoretical tools. My findings and predictions were collaboratively validated and biologically contextualized through multiscale experimental methods. First, I computationally discover that epigenetic switches buried within the nucleosome core alter DNA accessibility and the recruitment of essential proteins for mitosis. Next, using new computational tools, I report that centromeric nucleosomes are more elastic than their canonical counterparts and that centromeric nucleosomes rigidify when seeded for kinetochore formation. We conclude that the material properties of variants and binding events correlate with modified loading of transcriptional machinery. Further, I present my theoretical approach called Minimal Cylinder Analysis (MCA) that uses strain fluctuations to determine the Young's modulus of nucleosomes from all-atom molecular dynamics simulations. I show and explain why MCA achieves quantitative agreement with experimental measurements. Finally, the elasticity of hybrid nucleosomes in cancer is measured from simulation, and I implicate this oncogenic variant in potential neocentromere formation. Together, these data link the physics of nucleosome variations to chromatin states' plasticity and biological ramifications.Item TOWARD IN SITU MEASUREMENT OF LIQUID DENSITY USING OPTICAL KERR EFFECT SPECTROSCOPY(2016) Bender, John S.; Fourkas, John T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Optical Kerr effect (OKE) spectroscopy is a widely used technique for probing the low-frequency, Raman-active dynamics of liquids. Although molecular simulations are an attractive tool for assigning liquid degrees of freedom to OKE spectra, the accurate modeling of the OKE and the motions that contribute to it rely on the use of a realistic and computationally tractable molecular polarizability model. Here we explore how the OKE spectrum of liquid benzene, and the underlying dynamics that determines its shape, are affected by the polarizability model employed. We test a molecular polarizability model that uses a point anisotropic molecular polarizability and three others that distribute the polarizability over the molecule. The simplest and most computationally efficient distributed polarizability model tested is found to be sufficient for the accurate simulation of the liquid polarizability dynamics. The high-frequency portion of the OKE spectrum of benzene shifts to higher frequency with decreasing temperature at constant pressure. Molecular dynamics simulations of benzene are used to isolate the effects of temperature and density on the spectrum. The simulations show that, at constant density, the high-frequency portion of the spectrum shifts to lower frequency with decreasing temperature. In contrast, at constant temperature, the high-frequency portion of the spectrum shifts to higher frequency with increasing density. Line shape analyses of simulated spectra under isochoric and isothermal conditions shows that the effects of density and temperature are separable, suggesting that OKE spectroscopy is a viable technique for in situ measurement of the density of van der Waals liquids. OKE spectroscopy is then used to investigate the density of benzene confined in nanoporous silica. The high-frequency portion of the OKE spectrum shifts to the blue with increasing confinement, which is consistent with densification. Molecular dynamics simulations show that the tumbling vibrational density of states of benzene confined in silica pores exhibit behavior similar to that of the OKE spectrum. The dependence of the structure of the simulated liquid with increasing confinement resembles that of the bulk liquid at constant temperature and increasing density, further supporting the premise that benzene is densified upon confinement in silica pores.Item Molecular Dynamic Simulations of Nucleosomes and Histone Tails: The Effects of Histone Variance and Post-Translational Modification(2015) Winogradoff, David; Papoian, Garegin; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The packaging of genomic information and the regulation of gene expression are both fundamentally important to eukaryotic life. Meters of human DNA must fit inside the micron-diameter nucleus while still rapidly becoming available for templated processes such as transcription, replication, and repair. Therefore, the DNA-protein complex known as chromatin must dynamically transition between more compact, closed states and more accessible, open ones. To fully understand chromatin structure and dynamics, it is necessary to employ a multifaceted approach, integrating different general philosophies and scientific techniques that include experiment and computation. Since the DNA in chromatin is organized into arrays of nucleosomes, we take a bottom-up approach in this dissertation, striving first to understand the structure and dynamics of an individual nucleosome and subdomains thereof. Atomistic computational methods have provided useful tools to study DNA and protein dynamics at the nanosecond, and recently microsecond, timescale. In this dissertation, we present recent developments in the understanding of the nucleosome though atomistic molecular dynamics (MD) simulations. By applying different all-atom MD computational techniques, we demonstrate that replacing the canonical H3 histone with the centromere-specific variant CENP-A translates to greater structural flexibility in the nucleosome, that replacing H3 with CENP-A increases the plasticity of an individual histone dimer, and that the effects of acetylation on the H4 histone tail are cumulative and specific to lysine 16 mono-acetylation.