Chemistry & Biochemistry Theses and Dissertations
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Item Experimental and Theoretical Characterization of Effective Interactions Near 132Sn(1987) Stone, Craig A.; Walters, William B.; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, MD)Experimental investigations have been undertaken to study the multiplet structure in six nuclei near 132Sn: 132,130Sb, 131,129,127Sb, and 132Te. Experiments were performed using ion beams of mass-separated fission products produced by the TRISTAN mass separator at Brookhaven National Laboratory. Extensive four-detector gamma-gamma coincidences, gamma-multiscaling and conversion-electron data have been collected. Ultralarge shell model calculations were performed using the VLADIMIR shell model code on the Cray/CDC 7600 supercomputer system at Lawrence Livermore National Laboratory. These calculations were designed to look at the performance of the Kallio-Kolltveit and Siemen's g-matiix potentials on the 1-3 quasiparticle nuclides in the gddsh model space. Results show that realistic potentials work well on nuclei near 132Sn but show problems with 129,130Sn and 131Sb which can not be accounted for by core-polarization corrections. Problems are shown to be due to the use of a potential derived with the Scott-Moszkowski separation metl1od. The separation distance was demonstrated to have a weak dependence on the principal quantum number but a strong dependence on the orbital angular momentum. This suggests the Kallio-Kolltveit potential is underestimating the strength of the h11/2 interactions in 129,130Sn and 131Sb.Item Spacial and Temporal Variations in 36CI Deposition in the Northern United States(1994) Hainsworth, Laura J.; Mignerey, Alice C.; Chemistry and Biochemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md)Chlorine-36, a cosmogenic radioisotope, has been developed for use as a tracer in hydrological systems. The deposition of atmospheric 36Cl, although of primary importance to hydrological applications, has not been well studied. To begin to address this problem, 36Cl has been measured in monthly, wet-only, precipitation samples collected from February, 1991, to January, 1993, at the Elms Environmental Education Center in St. Mary's County, Maryland. In addition, bulk deposition samples were collected over a 1 y period at seven sites across the Northern United States and analyzed for 36CI. The mean, wet-only 36Cl/Cl ratio for the 2 y sampling period is 68±19 (x10 -15), and the mean 36 CI concentration is 1.2±0. 1 (x10 6) atoms/L. The 36Cl wet deposition flux data reveal a distinct seasonal deposition pattern, with peaks occurring in March and April. This pattern is attributed to stratospheric/ tropospheric exchange. The mean 36Cl wet deposition flux is 38.2±5 atoms/m2s. Comparison between wet-only and bulk deposition samples indicates that the difference accounts for approximately 25% of the total 36Cl deposition flux at the Elms site. A new model, using 90Sr to predict the 36CI deposition pattern, is developed to predict 36Cl/Cl ratios across the United States. Chlorine-36/Cl ratios in bulk deposition samples collected across the northern United States agree well with the model predictions. A mean global 36Cl production rate of approximately 28 to 38 atoms/m2s is indicated by these samples. A comparison between 36Cl concentrations in the Aquia and Magothy aquifers is southern Maryland and bulk deposition samples collected at the Elms, MD, site indicated that modern precipitation can account for the 36Cl content in the youngest water in these aquifers. Surface water samples from the Susquehanna River basin reveal 36 Cl and stable chloride concentrations an order of magnitude higher than in bulk deposition samples collected at State College, PA. The source of excess 36Cl in the Susquehanna is not known. Possible explanations include 'bomb-pulse' 36Cl and in-situ 36CI production in surface rocks.Item Development of single-neuron proteomics by mass spectrometry for the mammalian brain.(2021) Choi, Bok Dong; Nemes, Peter; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Single-neuron proteomics holds the potential to advance our understanding of important biological processes during neuron maturation and development. However, to characterize proteins from single neurons, further technological advances are still required. This dissertation discusses the development and application of single-cell mass spectrometry (MS) technologies to investigate proteins and its role in different neurons. The work presented herein demonstrates the strategies to develop and advance single-neuron analysis using capillary electrophoresis (CE)-MS. In addition, this work features several contributions to our understanding of neuron-to-neuron heterogeneity, providing new information to advance cell biology and neuroscience.Item COMBINED CHEMICAL AND ENZYMATIC APPROACHES TO PROTEIN GLYCOSYLATION(2021) Prabhu, Sunaina Kiran; Wang, Lai-Xi; Biochemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Glycosylation is a key post-translational modification of proteins and influences the structure and biological functions of proteins. Glycoproteins are significant in treating a variety of diseases and make up a large fraction of biotherapeutics. The carbohydrate structures on the proteins regulate biological activity and pharmacokinetic properties, thereby dictating the efficacy and cost of glycoprotein drugs. However, glycoproteins expressed in biological systems are heterogeneous in nature and impose a challenge to structure-function studies as well as design of potent therapeutics. Thus, developing tools to modulate the glycan structures on proteins is highly significant. In my thesis, we have explored biological and chemoenzymatic methods to generate homogeneously glycosylated therapeutic proteins. First, we designed a glycosylation machinery in Escherichia coli (E. coli) using an N-glycosyl transferase enzyme to transfer a sugar handle onto a model protein. The protein was then elaborated with a homogeneous glycoform using in vitro chemoenzymatic transglycosylation. Using this methodology, we produced a fully glycosylated human interferon alpha-2b that was biologically active and displayed significantly enhanced proteolytic stability. Next, we focused on expanding the toolbox of enzymes available to perform the chemoenzymatic glycan remodeling of proteins. Specifically, we compared the substrate specificities of the human α-L-fucosidase (FucA1) and two bacterial α-L-fucosidases (AlfC and BfFuc) with a panel of structurally well-defined core-fucosylated substrates. FucA1 was the only α-L-fucosidase to display hydrolytic activity towards full-length core-fucosylated glycopeptides and glycoproteins. Moreover, FucA1 showed low but apparent activity to remove core fucose from intact monoclonal antibodies. This finding reveals an opportunity to employ FucA1 to remove core fucose from therapeutic antibodies to improve their antibody-dependent cellular cytotoxicity. Finally, we explored modulation of core fucosylation of monoclonal antibodies through metabolic glycoengineering. We designed L-fucose analogs to potentially incorporate functionalized fucose into IgG-Fc glycan. We showed incorporation of a few fucose derivatives into antibodies and identified a concentration-dependent effect of some of the previously known analogs. While some of the novel compounds did not show effect, the study supplements the existing tools available for metabolic modulation of antibodies. In summary, these studies present feasible new approaches to produce therapeutic eukaryotic glycoproteins with desired, homogeneous glycosylation.Item BIOPHYSICAL STUDIES OF UBIQUITIN: FROM FOLDING TO PROTEIN ENGINEERING(2021) Camara, Christina M; Fushman, David; Biochemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The signaling protein ubiquitin is known for its ubiquity — existing in nearly all cel- lular compartments, holding a prominent role in major cellular signaling pathways and serving as a model system for protein folding. Herein, we honor this stature by exploring several aspects of the ubiquitin system form biophysical, structural, and computational per- spectives. Our efforts begin from the standpoint of protein engineering, where we extend ubiquitin’s function by installing a transition–metal binding motif and elevate it to the sta- tus of a metalloprotein. In doing so, we introduce novel spectroscopic behaviors, reactive propensities, and the capability to form non–canonical polyubiquitin chains — with appli- cations that span from molecular nanotechnology to synthetic biology. We then shift to foundational investigations of ubiquitin’s fold. By characterizing local degrees of freedom, we demonstrate how conformational motions of ubiquitin’s C–terminus can be controlled by the cellular microenvironment. This response, in turn, can regulate molecular recog- nition within the ubiquitination cascade. Finally, we approach global aspects of ubiquitin folding — exploring how a motif containing the C–terminus and the β5 strand might assem- ble into ubiquitin’s β –grasp architecture — with general lessons for ubiquitin–like proteins and other systems with an apparent two–state folding mechanism.Item Development of Next Generation Living Coordinative Chain Transfer Polymerization and New Polyolefin Materials Obtained Therefrom(2021) Wallace, Mark Alexander; Sita, Lawrence R; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The living polymerization of ethene, propene, higher carbon-number linear and branched chain α-olefins, and α,ω-nonconjugated dienes has provided the basis for the development of modern technological advances and achievements. The use of polyolefin materials is ubiquitous through the many plastic products produced on an over 300-million-metric-ton global scale annually. The sheer range and scope of these products is further underscored by the fact that such diversity is achieved from a very limited number of industrially relevant olefin monomer feedstocks. As such, continued advancement of polyolefin materials has been achieved through the design and validation of new polymerization methods and transition-metal catalysts that allow for the controlled production of polyolefins with tailored architectural features and physical properties. Furthermore, these methods and materials must generate the desired products in a fashion that is both cost effective and amenable to large scale production.Towards this goal, the work herein presents the design, validation, and implementation of ‘next generation’ living coordinative chain transfer polymerization (LCCTP) through five new polymerization methods for the synthesis of polyolefin materials with new functionalities, stereochemical configurations, optical activities, and with tailored molecular weight distribution profile and dispersity. These new methods include the design of a novel homochiral group 4 cyclopentadienyl, caproamidinate (CPAM) hafnium pre-initiator that exhibits unprecedented configurational stability. Most importantly, these new LCCTP methods allow for the generation of different classes of polyolefin materials in a controlled and scalable manner. Discussions concerning the design and application of these new methods, the materials they produce, and the future of these new advances will be presented.Item CHARACTERIZATION OF THE STRUCTURE AND BINDING OF BRANCHED K6/K48-LINKED AND BRANCHED K6/63-LINKED POLYUBIQUITIN CHAINS(2021) Abeykoon, Dulith Maduwantha Bandara; Fushman, David; Biochemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Ubiquitin (Ub) is an important post-translational protein modifier in eukaryotes. Post-translational modification with Ub is an essential process for eukaryotic cellular signaling including protein degradation, DNA repair, antigen-peptide generation and endocytosis. This post-translational modification with Ub occurs through ubiquitination where Ub attach as monoUb or polyUb chains. Ub form polyUb chains by forming covalent linkages between the C-terminus of one Ub and any of seven lysines or the N-terminus of other Ubs. Polyubiquitin chains can form homogeneous, heterogeneous, linear or branched chains, leading to diversity in polyubiquitin chain signaling outcomes. This diversity in signaling is due to the variety of conformations that arise based on the linkage specificity of the polyUb chains. Recently, branched K6/K48-linked polyubiquitins were shown to enhance deubiquitinating activity of UCH37 in the presence of Rpn13. To better understand the underlying structural mechanisms, here we determined the NMR structures of branched K6/K48-linked triubiquitin (Ub3) and discovered a previously unobserved interdomain interface between each of the distal ubiquitins and the proximal domain. We performed NMR binding assays to study the interactions of branched K6/K48-linked Ub3 with hHR23a UBA2, Rap80 tUIM and UCH37/Rpn13 complex. Binding studies of branched K6/K48-linked Ub3 to the UBA2 domain of the proteasomal shuttle protein hHR23A resulted in negligible differences between branched K6/K48-linked Ub3 and related dimers (K6-Ub2 and K48-Ub2). Interestingly, introducing hydrophobic patch surface residue mutations led to stronger affinity with both distal domains suggesting a change in the binding mode. Stronger binding affinity for K6/K48-linked branched Ub3 was observed with Rap80 tUIM. Moreover, deubiquitinating enzyme UCH37 (with Rpn13) showed strong affinity for both K6-linked and K48-linked distal domains, thereby suggesting a functional impact of this interdomain interface towards enhanced deubiquitinating activity of UCH37. Moreover, mutation studies of the hydrophobic patch residues of the proximal ubiquitin have shown the importance of the hydrophobic patch surface to maintain the interdomain interface of this branched trimer and for interactions with binding partners. Finally, initial studies done with the regulatory domain of the DNA repair protein p53 (p53c) have shown that p53c is a promising candidate for ubiquitination via non-enzymatic ubiquitination method introduced by our lab.Item INVESTIGATION OF ORDERED POROUS MATERIALS FOR LITHIUM AND MAGNESIUM IONS ELECTROCHEMICAL ENERGY STORAGE(2021) Henry, Hakeem Kimani; Lee, Sangbok; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)As portable electronics and electric vehicles become a more integral part of everyday life, rechargeable electrical energy storage devices (batteries) capable of providing greater energy and power densities will soon be necessary. Lithium-ion batteries (LIBs) have dominated this area of rechargeable energy storage devices since their commercialization in 1990. However, as electronic devices continue to advance, battery technology will have to go beyond conventional lithium-ion battery systems to power these devices. Among the many possible alternatives to lithium, magnesium is a promising candidate. In comparison to lithium, magnesium is more abundant, lower in cost, and more environmentally friendly. Magnesium batteries can also utilize a Mg metal anode which offers a high volumetric capacity and low standard reduction potential. Despite the potential benefits, Mg batteries suffer from several drawbacks. The three main issuesplaguing Mg batteries are (1) a lack of practical cathodes due to slow insertion kinetics of the divalent Mg2+ ion, (2) incompatibility between Mg electrolytes and high voltage cathodes, (3) and parasitic and passivating reactions occurring at the Mg metal anode surface. The work of this dissertation aims to address the Mg2+ insertion issue by developing modified cathodes with enhanced electrochemical performance. In the first study, the effect of structure and hydration on Mg2+ intercalation into amorphous and crystalline V2O5 films was systematically investigated by electrochemical methods. It was determined that the high water content of electrodeposited V2O5 films was the primary factor impacting Mg2+ intercalation, while the crystal structure played a secondary role. In the second study, an ordered mesoporous carbon (OMC) structure was grown on the surface of carbon nanotubes (CNT) to achieve a novel electrode architecture. The hybrid carbon structure allowed for fast ion diffusion and high electronic conductivity. The porous structure also served as an excellent host for the deposition of high-capacity cathode materials for an all-in-one electrode design. In the final study, the OMC synthesis method was paired with electrodeposited V2O5 protocol to further investigate the OMC electrochemical performance. Overall, the work of this dissertation contributes to the development and commercialization of rechargeable Mg batteries by elucidating a portion of this complex chemistry.Item LIGHT CONTROL OF CHEMICAL SYSTEMS: PHOTOCHEMICAL ELECTRON TRANSFER METHODS FOR RELEASING CALCIUM IONS AND THE PHOTOISOMERIZATION OF ALKENES TO MODULATE RHEOLOGICAL CHANGES.(2021) Heymann Loor, Romina R; Falvey, Daniel E; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Our research combines organic photochemistry with the engineering principles of rheology through the study of photorheological fluids (PR). The two photochemical systems researched show changes in the rheological properties brought about by the addition of light. The investigated systems are the photoisomerization of cinnamic acid derivatives in the surfactant, Cetyltrimethylammonium bromide (CTAB), and calcium release through degradation ethylenediaminetetraacetic acid (EDTA) caused by an electron transfer mechanism. The CTAB system shows how a change in molecular conformation can cause significant changes in the bulk property of a solution. The calcium EDTA system employs targeted electron transfer to cause calcium release, which gels the biopolymer alginate with inexpensive, readily available materials. Chapter 2 details how the orientational binding, intermolecular interactions, and molecular geometry of cinnamic acid derivatives contribute to the rheological changes in CTAB. 1H NMR titration studies in CTAB identified binding patterns of the additives in CTAB. From those studies orientational binding models were developed for trans-ortho-methoxycinnamic acid (tOMCA), cis-ortho-methoxycinnamic acid (cOMCA), meta-methoxycinnamic acid (mMCA), para-methoxycinnamic (pMCA), ortho-hydroxycinnamic acid (oCoum), meta-hydroxycinnamic acid (mCoum), and para-hydroxycinnamic acid (pCoum). 1H-1H 2D NOESY spectra identified through space intermolecular interactions occurring within the micelle. Preliminary data into possible π-anion interaction between tOMCA molecules within the micelle is presented. Photolysis confirmed the creation of cis isomers for all additives but also identified coumarin by-products for oCoum. B3LYP calculations indicated out-of-plane geometry for all the cis isomers and possible intramolecular hydrogen bonding of oCoum. Finally, a model of binding interactions that lead to changes in the packing parameter of the surfactant and, therefore, a change into wormlike micelles for tOMCA versus cOMCA is introduced. In chapters three and four, we investigated calcium release using sensitizers that promote photoinduced electron transfer. Anthraquinones derivatives were shown in Chapter 3 to release calcium in stoichiometry amounts with UV light irradiation. In Chapter 4, flavins produced 1000-fold calcium release to sensitizer concentration in the visible light spectrum. In both chapters, there are detailed calcium release studies, degradation studies, and alginate experiments. We present calcium release studies at acidic and neutral pH, quantum yields, degradation of EDTA, sensitizer reoxidation studies, sensitizer degradation data, fluorescence, and transient spectra. While enough calcium was released to produce alginate gels, none were made in vitro at neutral and acidic pH.Item MECHANISMS AND RATIONAL CATALYST DESIGN OF ORGANIC TRANSFORMATIONS FOR THE SYNTHESIS OF NEW C-C AND C-X BONDS(2021) Rotella, Madeline Elizabeth; Gutierrez, Osvaldo; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The creation of new C-C or C-X bonds, where X can be oxygen, nitrogen or fluorine, is vital to organic synthesis and the discovery of new methods for complex molecule synthesis. In many cases, the mechanism of these transformations is not investigated, although an understanding of the underlying mechanism would allow for rational design of new catalysts and would lead to the development of novel reactivity. Computational studies probing the mechanisms of valuable synthetic methods including C-H oxidation, organocatalysis, nickel photocatalysis, alkyne metathesis and multicomponent reactions are presented. Specifically, computational methods were used in the development of a novel tetradentate amine iron (II) catalyst for the promotion of C(sp3)-H oxidation (Chapter 1). Next, the mechanism of an organocatalyzed amination was studied thoroughly with density functional theory (DFT) calculations in combination with molecular dynamics simulations to develop a predictive model for reactivity for use in the creation of new catalysts in the field of amination chemistry (Chapter 2). Additionally, the mechanism of a regio- and enantioselective iridium-catalyzed asymmetric fluorination was studied, with an emphasis on determining the role of the trichloroacetimidate group in the reaction (Chapter 3). Further, the mechanisms of various transition metal-catalyzed C-C bond formations were studied through computationally. First, a photoredox/nickel-dual catalyzed Tsuji-Trost reaction was studied through DFT and DLPNO-CCSD(T) calculations to investigate the stereoselectivity of the reaction as well as the order of reaction events. Next, a photoredox/nickel-dual catalyzed C-C bond formation using oxanorbornadienes as electrophilic coupling partners was investigated computationally (Chapter 4). Additionally, the mechanism of tungsten- and molybdenum-catalyzed alkyne metathesis as well as the difference in reactivity between the two metals was explored (Chapter 5). A nickel-catalyzed diarylation of alkenes was studied computationally, with particular emphasis on the role of the phosphine ligand in controlling regioselectivity (Chapter 6). Finally, an iron-catalyzed dicarbofunctionalization of vinyl ethers with aryl Grignard reagents and alkyl halides or (fluoro)alkyl halides was developed experimentally (Chapter 7).