Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1987. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Bibliography: leaves 225-230. / by Jeffery Thayer Davis. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1998. / Includes bibliographical references. / by Melanie Sarah Bartow Wills. / Ph.D.

Thesis (S.M. in Inorganic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013. / "February 2013." Vita. Cataloged from PDF version of thesis. / Includes bibliographical references. / Proton-Coupled Electron Transfer (PCET) is an important mechanistic motif in chemistry, which allows for efficient charge transport in many biological systems. We seek to understand how the proton and electron motions are coupled in a bidirectional system allowing for individual turning of the kinetics and thermodynamics. The target of interest is a biomimedic heme system allowing for a detailed mechanistic study of the formation of the oxidation states of heme, of particular interest the highly reactive Fe(IV)=O species. The bidirectional model is prepared using a hangman porphyrin with an axially coordinated to the metal center, and the electron transfer event is triggered by excitation of the porphyrin. The synthesis of this motif is discussed as well as initial studies into the binding of a coordinated electron acceptor to the metal center. In the future, the excited state of the acceptor will be used to trigger the electron transfer portion of the PCET event. To understand the signatures of different electron acceptors and binding to the metal center, a redox inactive zinc porphyrin is used as a model to allow for longer excited state lifetimes and well known transient signatures. Three diimide acceptors have been coordinated through a pyridine ring to the metal center of the porphyrin, and electron transfer was triggered both by excitation of the porphyrin and the acceptor. Lifetimes of the charge separated state were determined using picoseconds and nanosecond transient absorption. The acceptors are then coordinated to a symmetrical iron porphyrin in an attempt to understand the behavior of charge separation in the more complicated open d shell system. Spectroscopic data of both systems is shown. / by Christina J. Hanson. / S.M.in Inorganic Chemistry

Thesis: S.M., Massachusetts Institute of Technology, Department of Chemistry, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 40-42). / Flow-IEG has emerged as a powerful platform for the production of sequence-defined macromolecules and has demonstrated the utility of adapting continuous-flow methodologies to the production of materials for structure/function analysis. Our Flow-IEG system has been expanded to include both the ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC), as well as a more operationally simple version of the copper-catalyzed analogue (CuAAC). These advances have enabled the rapid synthesis of a library of oligomers with systematic variations in triazole connectivity, allowing us to probe the consequences of sequential connectivity on material properties. In our investigation, we found that the crystallinity of the synthesized materials increased with higher proportions of 1,4- to 1,5-triazoles, from which a set of predictive design rules was developed and applied to a second library of diblock copolymers. Furthermore, we discovered that the crystallization properties of these macromolecules were highly dependent on both their monomer sequence and triazole substitution pattern. The results of these studies are reported herein. / by Amanda C. Wicker. / S.M.

Includes bibliographical references. / Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005. / "February 2005." Vita. / (cont.) Such therapeutic approaches require an understanding of the mechanisms regulating stem cell differentiation. The second part of this thesis investigates the role of HSGAGs in embryonic stem cell differentiation into endothelial cells. Differentiation of stem cells was accompanied by increases in the transcript levels of key HSGAG-biosynthetic enzymes, and the quantity of cell surface HSGAGs. Differentiation into endothelial cells was inhibited by ablation of the HSGAG-biosynthetic machinery by chlorate treatment, or by the enzymatic degradation of the HSGAGs. Exogenous addition of heparin to chlorate-treated cells partially restored differentiation into endothelial cells. These effects were mirrored in phospho-ERK levels, suggesting the involvement of the MAPK pathway. These results suggest that stem cell differentiation can be regulated by modulating the HSGAG moiety and this opens up new treatment modalities for cancer therapy and regenerative medicine. / The new paradigm is that cancers may originate from stem cells, and that terminal differentiation of stem cells is a possible treatment for cancers. Understanding the origin of cancers requires elucidation of factors causing genetic rearrangements. The first part of this thesis explores the effects of NO on homologous recombination in embryonic stem cells. Using terminal differentiation of stem cells as a therapy for cancer necessitates an understanding of factors governing their differentiation. The second part of this thesis explores the effects of heparan sulfate glycosaminoglycans (HSGAGs) on stem cell differentiation. Inflammation is increasingly recognized as an important risk factor for cancer. During inflammation, macrophages secrete NO, which reacts with superoxide or oxygen to produce ONOO⁻ or N₂O₃, respectively. Although ONOO⁻ and N₂O₃ are potent DNA damaging agents, little was known about the ability of these agents to induce homologous recombination in mammalian cells. Homologous recombination events are a significant source of mutations that are likely to contribute to initiation and progression of some cancers. In the first part of this thesis, the recombinogenic potential of ONOO⁻ and N₂O₃ was characterized by sister chromatid exchanges, chromosomal direct repeat substrate and interplasmid recombination assays. Our results show that on a per lesion basis, ONOO⁻ -induced oxidative base lesions and single strand breaks are more recombinogenic than N₂O₃-induced base deamination products. These results are in accordance with the model that ONOO⁻ -induced recombination may contribute to inflammation-induced cancer. Directed differentiation of stem cells holds an immense potential for regenerative medicine as well as cancer therapy. / by Tanyel Kiziltepe. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1995. / Includes bibliographical references. / by Benjamin Peter Warner. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2017. / Cataloged from PDF version of thesis. Page 186 blank. / Includes bibliographical references. / Natural proteins are comprised primarily of (L)-amino acids. (D)-amino acids are rare in protein structures. Solid-phase peptide synthesis (SPPS) and native chemical ligation enable the total chemical synthesis of proteins. Using these techniques, it is possible to design and study polypeptides foreign to Nature. Herein, I describe the investigation and application of proteins simultaneously comprised of (L)- and (D)-amino acids. SPPS has traditionally been a time intensive endeavor. Recently, the Pentelute laboratory described a flow-based system that reduces the time required to synthesize a polypeptide by over an order of magnitude. We have systematically studied variables that influence peptide quality with this system. From these efforts, we established protocols used in the synthesis of heterochiral polypeptides. We proceeded to study two different heterochiral systems. In the first system, we examined folding of (L)-proteins containing loops of (D)-amino acids, and vice-versa. Protein loops are important structural features that mediate protein-protein interactions. Using Ecballium elaterium trypsin inhibitor II (EETI-ll), we discovered that strategic incorporation of linkers such as P-alanine or glycine can facilitate efficient folding of heterochiral proteins. We used NMR spectroscopy and molecular dynamic simulations to interrogate the structure and folding pathway of one such protein that possesses a (D)-amino acid core and a loop with 5 (L)-amino acids, 2 P-alanine, and 1 glycine. We also determined that our heterochiral proteins were more resistant to proteolysis than natural proteins. In the second system, we examined heterochiral antibody-drug conjugates (ADCs) for the treatment of P. aeruginosa infection. New therapeutic modalities are needed to address bacterial resistance to conventional antibiotics. We developed a biologically expressed antibody that targets P. aeruginosa and bears antimicrobial peptides chemically synthesized from (D)-amino acids. In vivo studies demonstrated that heterochiral ADCs are effective at reducing the bacterial burden in a murine lung infection model. These ADCs bind a conserved glycan of P. aeruginosa lipopolysaccharide and directly kill the pathogen through a mechanism of membrane disruption. Our lead heterochiral ADC candidate is being advanced through additional pre-clinical studies. / by Surin Khai Mong. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1997. / Includes bibliographical references. / by Linda Szabo Shimizu. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2004. / MIT Institute Archives copy: pages 215 to 304 bound in reverse order. / Includes bibliographical references. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Many of the remarkable physical and chemical properties of liquid water are due to the strong influence hydrogen bonds have on its microscopic dynamics. However, because of the fast timescales involved, there are relatively few experimental techniques capable of directly probing rearrangements of water's hydrogen bonded network. In this thesis, I investigate ultrafast intermolecular dynamics of water with time-resolved Raman and time-resolved infrared spectroscopies. These two sets of measurements provide a complimentary view of the collective and local behavior of molecular motions. Using a novel Raman technique, spatially masked optical Kerr effect spectroscopy, I first measured interaction-induced fluctuations in the isotropic many-body polarizability of water and several other liquids. In contrast to the behavior of simple liquids, the isotropic response of water is exceedingly fast and distinct from the well-known anisotropic response. I then designed and built an optical parametric amplifier that produces sub-50 fs pulses of mid-IR light to investigate the intermolecular dynamics of water through their effect on the OH oscillator of HOD in D20. By analyzing the results of three-pulse vibrational echo and polarization- selective pump-probe measurements with a comprehensive theory to describe vibrational dynamics, I extracted the timescales for vibrational relaxation, dephasing and molecular reorientations. / (cont.) At short times, vibrational dephasing reflects an underdamped 180 fs hydrogen bond oscillation, but the long time behavior indicates collective structural reorganization of the hydrogen bond network a 1.4 ps timescale. The anisotropy decays on timescales of 50 fs and 3 ps, which are attributed to librations and rotational diffusion, respectively. Lastly, I used two-dimensional infrared spectroscopy to investigate the frequency dependence of the dynamics. Preliminary results reflect a distribution of timescales for both local motion and collective reorganization. / by Christopher J. Fecko. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1997. / Includes bibliographical references (leaves 150-155). / by Zhonghua Pei. / Ph.D.