Chemistry & Biochemistry Theses and Dissertations

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    (2023) Pawloski, Westley; Fushman, David; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The post-translational modification of proteins with ubiquitin (Ub) can induce a multitude of cellular signaling processes. Ubiquitination involves the attachment of the C-terminus of Ub to lysines on the substrate protein through an isopeptide linkage. This process is facilitated by a multitude of enzymes which work in concert to write and erase these linkages. The power of Ub signaling is that Ub itself can be modified by additional Ub units to generate polyubiquitin chains through any of the seven lysines or N-terminal amine, and each of these attachment points produces polyubiquitin (polyUb) chains with unique orientations of the internal Ub. This allows for K48 polyUb chains to mark a substrate for proteasomal degradation or K63 polyUb chains to trigger DNA repair and maintenance processes. The Ub signaling system is an amalgamation of post-translational modifications, enzymatic activity, and carefully curated protein-protein binding interactions for this small 76 amino acid protein. My work presented in this disseration involves harnessing the power of nuclear magnetic resonance (NMR) experimentation to observe interactions of multiple components of the Ub system with site-specific resolution and selective kinetics. To this end, I have implemented some standard and atypical NMR experiments to observe the potential for carbon dioxide carbamates to modulate the Ub signaling system. I have determined the kinetics of the enzymatic Ub-activating process, and this was extrapolated to understand how ubiquitiun-like proteins, which share a similar fold to Ub, are discriminated from erroneously taking the place of Ub. I have solved the solution structure of an unusual ubiquitin-like domain and explored how it interacts with Ub. Lastly, I will report on the implementation of an unnatural amino acid that is a photosensitive cross-linker and demonstrate that this technology can be used to detect novel ubiquitin-binding proteins.
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    Phase Transitions Affected by Molecular Interconversion
    (2023) Longo, Thomas; Anisimov, Mikhail; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Typically, pure substances may be found with only one gaseous or liquid state, while their solid state may exist in various polymorphic states. The existence of two distinct liquid forms in a single component substance is more unusual since liquids lack the long-range order common to crystals. Yet, the existence of multiple amorphous states in a single component substance, a phenomenon known as "liquid polyamorphism," has been observed or predicted in a wide variety of substances. In contrast to standard phase transitions, it has been suggested that polyamorphic liquid-liquid transitions are caused by the interconversion of molecular or supramolecular states. To investigate this phenomenon, a nonequilibrium thermodynamic model was developed to quantitatively describe the interplay between the dynamics of molecular interconversion and fluid-phase separation. The theory has been compared to a variety of interconverting systems, and has demonstrated a quantitative agreement with the results of Monte Carlo and Molecular Dynamics simulations. In this thesis, it is shown that there are two major effects of molecular interconversion on the thermodynamics and the kinetics of fluid-phase separation: if the system evolves to an equilibrium state, then the growth of one of the alternative phases may result in the destruction of phase coexistence - a phenomenon referred to as "phase amplification." It is demonstrated that depending on the experimental or simulation conditions, either phase separation or phase amplification would be observed. Previous studies of polyamorphic substances report conflicting observations of phase formation, which may be explained by the possibility of phase amplification occurring. Alternatively, if the system evolves to a nonequilibrium steady state, the phase domain growth could be restricted at a mesoscopic length scale. This phenomenon (referred to as "microphase separation") is one of the simplest examples of steady-state dissipative structures, and may be applicable to active matter systems, hydrodynamic instabilities, and bifurcations in chemical reactions, in which the nonequilibrium conditions could be imposed by an external flux of matter or energy.
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    (2023) McDonnell, Shannon Marie; Blough, Neil V; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Chromophoric dissolved organic matter (CDOM) is a large portion of the open ocean dissolved matter pool which contributes largely to ocean color. The composition and distribution of CDOM is essentially controlled by in-situ biological production, terrestrial inputs, photochemical degradation, and microbial consumption. Estuarine environments contain particularly diverse CDOM composition due to their large variety of inputs and shoreline land usage in addition to the mixing of freshwater and salt water. Developing a further understanding of CDOM variation and composition will help develop and improve satellite remote sensing algorithms, help us understand CDOM’s role in the global carbon, nitrogen, and oxygen cycles, and may help to prioritize in-situ sampling for water quality monitoring in areas of concern. The use of inherent optical properties combined with pH titration and chemical reduction with sodium borohydride (NaBH4), helps to probe the molecular composition of CDOM and its spatial variability. Detailed studies of CDOM from the Chesapeake Bay are limited with many studies only investigating the main channel of the Bay and neglecting the various tributaries. Also, there is a lack of studies which specifically probe the molecular composition of the CDOM samples. To address this, an in-depth analysis of the optical properties of CDOM and C18 extracted organic matter (C18-OM) from the Chesapeake Bay, focusing on various inputs, was performed. Chemical reduction with NaBH4 and pH titration were employed to probe the presence of specific functional groups and their contribution to overall optical properties, and how they vary between locations. Spectral slope (S300-700), E2:E3 absorption ratio, fluorescence intensity, and apparent quantum yield of fluorescence (AQY) were used to analyze 170 samples from various tributaries in the Chesapeake Bay. Overall, this study suggested 1) there may be multiple inputs of CDOM within the Chesapeake Bay 2) the Top of the Bay and central channel of the Bay are impacted by the heavy terrestrial input from the Susquehanna River 3) A lack of correlation between phytoplankton fluorescence and CDOM absorption suggest phytoplankton are not an immediate source of CDOM within the Chesapeake Bay and 4) removal of protein and phytoplankton fluorescence after sample filtration indicates these species must exist in aggregates >0.2 µm. Optical analysis combined with pH titration and NaBH4 reduction investigated the variation between 9 C18-OM extracts from various regions in the Chesapeake Bay and a humic material standard Suwannee River Fulvic Acid (SRFA). Additionally, this study investigated the validity of the Charge-Transfer (CT) model using the optical properties of model compounds. This study suggested 1) certain absorbing and emitting species are lost during C18 extraction but extracts are still representative of their CDOM 2) nearly identical optical responses to pH titration and NaBH4 reduction suggest similar chromophore content throughout the Chesapeake and 3) CT interactions leading to long wavelength absorption are more prevalent in Suwannee River Fulvic Acid (SRFA) than they are in the Chesapeake. To compare the molecular and optical properties of the Chesapeake Bay to other locales, these extracts were compared to extracts from the Delaware Bay (DEL), Equatorial Atlantic Ocean (EAO) and North Pacific Ocean (NPO) in addition to reference materials Suwannee River Fulvic Acid (SRFA), Pony Lake Fulvic Acid (PLFA), and Elliott Soil Humic Acid (ESHA). This study showed 1) composition of deprotonatable and reducible chromophores within the Chesapeake and Delaware Bays is nearly identical but different from the oceans 2) despite being estuaries and containing a mixture of fresh and ocean water, CDOM within both Bays looks terrestrially dominated 3) deep ocean extracts from the Atlantic and Pacific exhibit similar optical response to pH titration, NaBH4 reduction, and NaBH4 reduction combined with pH titration suggesting the similarity of deep ocean waters from both ocean basins.
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    (2023) Gutierrez Razo, Sandra Abigail; Fourkas, John T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The goal of this project is to create thin films to improve resolution for 3-color lithography (3CL). Lithography is a technique that is used to pattern semiconductor chips. The current methods used to manufacture chips use deep and extreme ultraviolet light to create patterns on a photoresist. 3CL is an alternative that creates patterns using easily-accessible visible light instead of dangerous radiation that requires specialized and prohibitively expensive equipment. This work focuses on improving the resolution of the 3CL technique by using thin negative tone acrylate photoresist films. Modern microelectronic devices require semiconductor chips that have individual features less than 100 nm wide and patterns with features that pack closely together. The industry is moving to shorter wavelengths because feature size is directionally proportional to the wavelength of the light used. However, 3CL uses visible light, which has larger wavelengths than the desired feature size. One way to reduce the size of features is to shape and overlap the beams so that not all irradiated areas result in fabricated features. Two beams are used to excite the photoinitiator in the photoresist to initiate radical polymerization in the acrylate monomers. The third beam is used to deactivate the photoinitiator, thus inhibiting polymerization before it can occur. Another requirement for semiconductor chip patterns is high resolution, or closely packed features. To prevent unwanted polymerization between features in 3CL, and thereby increase resolution, initiation and deactivation should occur from different photoinitiator excited states. Therefore, a 3CL photoinitiator should have a long-lived chemically inactive excited state where either deactivation can relax it back down to the ground state, or further excitation can bring it to the chemically active excited state. We examine isopropylthioxanthone (ITX) and its excited states to probe for 3CL behavior. Deactivation limits the feature width, but the deactivated features in the bulk material are taller than their width and collapse. Thin films are employed to correct the aspect ratio and further improve resolution. This project focuses on ITX’s performance as a 3CL photoinitiator, the procedure to produce 40 nm thin films, and how polymerization and deactivation are different in thin film samples compared to the micron-thick bulk samples.
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    (2023) Kramer, Morgan; Vedernikov, Andrei N; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The use of platinum group metals for the activation and functionalization of C-H bonds has been a topic of substantial interest over the past 60 years. Specifically, platinum-based complexes represent a particularly promising avenue due to their ability to form air- and water-stable species that are capable of reacting with some of the most inert C-H bonds within organic substrates. Over the decades of research contributing to this field, platinum complexes have frequently been angled towards fundamental mechanistic analysis of homogeneous C-H bond activation. In turn, the development of homogenous PtII-based catalytic systems has remained underdeveloped for the practical applications in C-H bond functionalization and, in particular, deuteration of complex organic molecules, including pharmaceuticals. The latter direction is now attracting a significant interest by the pharmaceutical industry. In this work the kinetic and thermodynamic selectivity of our new catalyst, a Pt(II) sulfonated CNN-pincer complex 1.5, in the H/D exchange reaction between aromaticsubstrates and wet TFE-d1 was screened across thirty-four aromatic substrates with the catalysts TON up to 300 (Chapter 2). A kinetic preference of 1.5 for electron-rich C-H bonds and substrates was firmly established and a novel scale of Hammett-like σXM constants was introduced to characterize the reactivity of the substrates’ C(sp2)–H bonds in transition-metal-mediated C-H activation. To greatly enhance our PtII catalysts’ useful life, we used their rigid covalent immobilization to mesoporous silica nanoparticles (immobilized complex 3.5). The resulting robust material served as an efficient H/D exchange catalyst utilizing cheaper sources of exchangeable deuterium, AcOD-d4, and D2O, with the catalyst’s TON up to 1600 (Chapter 3). To understand our novel catalyst’s structure – activity relationship, a series of benzene fragment – R-substituted analogs of 1.5 (R = MeO, tBu, iPr, F, Cl, CF3) were synthesized and explored in the H/D exchange of a series of aromatic compounds (Chapter 4). Surprisingly, the complex 4.1-tBu (R = tBu) stood out as a most robust homogeneous catalyst compatible with AcOD-d4 and D2O at 120 oC as deuterium sources that can work under air. Thanks to this finding, the substrates scope for the H/D exchange with AcOD-d4 catalyzed by 4.1-tBu was expanded to include eight pharmaceuticals, some alkenes, with signs of engagement of some C(sp3)-H bond donors. A novel photo-induced (violet light) room temperature H/D exchange catalyzed by 4.1-OMe was discovered with a substantially different substrate selectivity, as compared to the thermal reaction at 80 oC. These observations may provide some important insight into the mechanism of PtII-mediated C-H activation. Finally, Chapter 5 summarizes the results of this work and suggests some future directions for this area of research.