Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1998. / Includes bibliographical references. / by Jonas Christopher Peters. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1962. / Vita. Appendix contains numerous pamphlets. / Includes bibliographical references. / by Paul Clifton Rogers. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2012. / "June 2012." Cataloged from PDF version of thesis. / Includes bibliographical references. / Temperature-jump (T-jump) two-dimensional infrared spectroscopy (2D IR) is developed, characterized, and applied to the study of protein folding and association. In solution, protein conformational changes span a wide range of timescale from nanoseconds to minutes. Ultrafast 2D IR spectroscopy measures time-dependent structural changes within the protein ensemble by probing the frequency changes associated with amide I backbone vibrations. Combining 2D IR with a perturbing laser-induced T-jump enables the study of conformational dynamics from 5 ns to 50 ms. To access a finer time-sampling of the conformational evolution, a one-dimensional variant of 2D IR, heterodyne-detected dispersed vibrational echo spectroscopy (HDVE), is implemented. The framework for interpreting transient HDVE and 2D IR spectra is developed, and we propose a method to remove the linear absorption distortions along both frequency axes. We first present the T-jump 2D IR spectra of a dipeptide to reveal the general amide I baseline response expected in the absence of conformational change. To facilitate the analysis of T-jump data, singular value decomposition (SVD) is employed for reducing noise, identifying the number of distinguishable states, and separating spectral changes based on shared timescales. Finally, T-jump 2D IR spectroscopy is applied to study the unfolding of ubiquitin, disordering of the 12-residue p-hairpin peptide trpzip2 (TZ2), and the dissociation of insulin dimers to monomers. Experimental results for ubiquitin highlight the importance of linear absorption corrections for interpretation of the data. In response to the T-jump, 2D IR results indicate p-sheet structure melts in ubiquitin with a small amplitude (~10 gs) and large amplitude (17 ms) response. Isotope-labeling T-jump experiments on TZ2 allow for the proposal of a free energy surface in which transitions from a native and misfolded state proceed through a disordered hub-like state with a 1-2 gs timescale. Multiple timescales are observed in the T-jump induced dissociation of insulin. Based on their spectral features and concentration dependence, the insulin timescales can be assigned to dissociation, disordering, and oligomerization processes. With these applications, we demonstrate the capability of T-jump 2D IR spectroscopy to reveal detailed molecular dynamics. / by Kevin C. Jones. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Vita. / Includes bibliographical references. / Human dietary exposure to aflatoxin B1 (AFB1) is linked to hepatocellular carcinoma (HCC), especially in areas where significant hepatitis B infection is concurrent. Susceptibility to this carcinogen varies among species. Neonatal mice, like rats and most other species, are highly sensitive to the hepatotoxic and carcinogenic effects of AFB1; unlike other species, however, maturation of the mouse is accompanied by a transition to almost complete resistance to the toxin over a short period of a few weeks. This study compares age-specific differences in hepatic gene expression in B6C3F1 mice as they transition from their sensitive to refractory periods of life. Herein, 1-day old mice (highly susceptible to acute AFB1 toxicity), 4-day old mice (modestly affected by toxicity but highly susceptible to tumorigenesis), 7-day old mice (even less sensitive to toxicity and carcinogenesis) and adult mice (highly resistant to both the toxic and carcinogenic effects of AFB1) are compared. At each time point the AFB1-DNA adduction level was used as a predictive biomarker of genetic risk. Enzymes that detoxify the AFB1-8,9-epoxide, the metabolite of AFB1 responsible for genetic effects, were expressed at lower levels in neonates, resulting in formation of a high level of DNA adducts; this parameter, together with markers of aggressive cell proliferation, correlated well with the enhanced susceptibility of the neonates. AFB1 treatment of neonates caused strong and wide ranging transcriptional responses. / (cont.) Newborn animals,in response to AFB1, robustly expressed genes involved in cell cycle regulation, apoptosis and, in some cases, oncogenesis; such changes were absent in AFB1-treated adult mice, which is in line with their low sensitivity to the toxin. This study revealed a dynamic pattern of changes in gene expression that accompanied the diminished sensitivity of the mouse to this potent human carcinogen during the aging process, shedding light on the basis of AFB1 susceptibility. In addition, gene transcription profiles of three mouse strains were compared to probe the genetic basis of their differential susceptibilities to spontaneous and inducible HCC. In parallel, a 1.6-fold difference in AFB1-DNA adduct level was observed between the HCC-susceptible C3H/He strain and the HCC-resistant C57BL/6 strain. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2015. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student-submitted PDF version of thesis. / Includes bibliographical references. / Part I: An brief introduction to dynamic nuclear polarization (DNP) is provided including a discussion of polarization mechanisms and development of new polarization methods in a historical context. Efficient synthesis of highly water-soluble BDPA derivatives that preserve the desirable DNP properties of BDPA and expand its application to aqueous systems is described. The narrow line radical applications in magnetic resonance spectroscopic imaging (MRSI) are investigated focusing on thermal mixing (TM) DNP of pyruvic acid. Design considerations and efforts toward the synthesis of bi- and multiradicals for Cross Effect (CE) DNP, and experiments performed with mixtures of radicals and covalently bound hetero-biradicals are reported. Part II: Indoles are important heterocycles because of their presence as common structural motifs in natural products and pharmaceutical candidates. Second generation Danheiser benzannulation-tandem cyclization approach was developed and applied toward the synthesis of highly substituted indoles. Substrate synthesis, benzannulation results and product elaboration are described. / by Olesya Haze. / Ph. D.

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1996. / Includes bibliographical references (p. 129-130). / by Venkatesh Locharla Murthy. / M.S.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1994. / Includes bibliographical references. / by Ernest James Mueller. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2004. / Vita. / Includes bibliographical references. / Three principal analytical methods: circular dichroism (CD), hydrogen exchange, and the t/c ratio of Ac-Hel, a helix stabilizing N-cap, are used in combination to quantify fractional helicity in order to determine the intrinsic helical propensity of an alanine residue, free from the hydrophobic packing within proteins. Constructed cross checks between these methods add rigor to propensity assignments and present the opportunity to resolve controversies regarding helical propensities and limiting ellipticities used in CD. Unlike proteins that approximate a single folded conformation, simple helical polyalanine peptides exists as a manifold of partially helical conformers. The Ac-Hel template characterizes short helical conformations that exist within larger manifolds. Using an isolation and solubilization methodology, t/c measurements of Ac-Hel alanine conjugates up to 14 residues indicate an increase in the helical propensity with length that was previously undetected for 6 residue conjugates. A constructed cross check of t/c with circular dichroism ellipticities indicate that both methods provide consistent measurements of peptide helicity. Protection factors, measured by hydrogen exchange, assign site helicities that provide incisive information about the manifold of helical conformers for a fifteen residue helical alanine region. Protection factor measurements are also used to corroborate the length dependence seen by t/c over an extended length series between 5 and 25 alanine residues. A joint analysis of the experimental CD ellipticity and the fractional helicity as determined by hydrogen exchange is tested as a cross check to calibrate CD. Long helical peptides with moderately stabilizing N-caps were previously shown to exceed a fractional helicity / (cont.) of 1.0. The conformational averaging seen for intrinsic polyalanine helices can be dramatically reduced by highly stabilizing N- and C-terminal caps. An octaalanine core, stabilized by Ac-[superscript]β aspartyl-Hel as an N-cap and β-amino alanine as a C-cap, also exceeds current literature standards for factional helicity. As a proof of principle, hydrogen exchange measures factional helicity approaching 0.95 for all eight alanine residues. A complete series of this type is proposed to establish the perresidue molar ellipticity for a infinite length helix ( [theta][sub][infinity, 222]) and its length dependence. / by Robert J. Kennedy, III. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2006. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Vita. Page 257 blank. / Includes bibliographical references. / Metal complexes of the macrocycle porphyrinogen (calix[4]pyrrole) are studied with an emphasis on the redox activity ("non-innocence") of the ligand (Chapter I). Porphyrinogen complexes of spherical, redox-inert metal dications exist in three oxidation states, dianionic, neutral, and dicationic, characterized structurally by zero, one, and two direct bonds between adjacent pyrroles, respectively. All three are isolated on the preparative scale, and interconverted electrochemically (Chapter II). Each carbon-carbon bond functions as a reservoir of two redox equivalents. The neutral oxidation state exhibits an optical intervalence charge transfer transition, characteristic of ligand-based two-electron mixed valency (Chapter III). Dianionic zinc porphyrinogen reacts with carbon dioxide, and neutral zirconium(IV) porphyrinogen with dioxygen. Two zirconium porphyrinogen units can carry a water molecule as an oxo bridging the metals and two protons on the ligands (Chapter IV). Iron porphyrinogen has three available oxidation states, a dianion, a monoanion, and a dication. The interconversion of the latter two is a selective three-electron transformation, preparatively and electrochemically (Chapter V). complex are largely decoupled from each other and can be chosen independently (Chapter IX). / (cont.) Crystallographic analysis shows that both anionic oxidation states contain the reduced ligand, whereas the dicationic state is based on the oxidized ligand (with two C - C bonds). Paramagnetic NMR confirms the structures in solution. Spectroscopies (EPR, Mössbauer) allow the assignment of well-defined individual oxidation and spin states states for the metal within each overall oxidation state of the complex (Chapter VI). The iron porphyrinogen dication is an oxidant based on an iron(II) center; it oxidizes iodide to diiodine (Chapter VII). The cobalt(II) porphyrinogen dianion can take up two protons, then photoreact to yield reduction of at least one proton to a metalbound hydride, as evidenced by infrared spectroscopy (Chapter VIII). Overall, the results afford a picture of metal-porphyrinogens including structure, electronic structure, and reactivity. The ligand supplements the central metal ion by functioning as a multielectron reservoir. Therefore, the (metal-based) coordination and (ligand-based) redox properties of a given porphyrinogen / by Julien Bachmann. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1996. / Includes bibliographical references. / by Brendan Francis Bellew. / Ph.D.