Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references. / An estimated 35% of the human proteome is intrinsically disordered. Disordered proteins play a key role in physiologic and pathologic regulation, recognition, and signaling making protein disorder the subject of increasing investigation. Since disordered samples do not generate x-ray quality crystals and since they have conformations that interconvert faster than the time resolution of NMR or ESR, little is known about their structure or function. By combining isotope-edited two-dimensional infrared spectroscopy (2D IR) with spectral modeling based on molecular dynamics simulations, this work will show that one can measure the residual structure and conformational heterogeneity of a putatively disordered sequence. This methodology was first used to study the structure and dynamics of the tryptophan zipper 2 (TZ2) peptide. The TZ2 peptide is a 12 residue engineered sequence that employs the "tryptophan zipper" motif to stabilize a p-hairpin fold. For this work five isotopologues of TZ2 were synthesized, the p-turn label K8, the midstrand labels T10 and T3T1O, the N-terminal label S1, and the unlabeled peptide UL. Temperature dependent FTIR and 2D IR studies in conjunction with modeling revealed that the TZ2 peptide at low temperatures exists as a folded peptide with a type I' turn and a small previously unobserved subpopulation of a bulged loop structure. Upon heating a fraying of the peptides termini is observed, in addition the population of the type I' turn increases relative to the population of the bulged turn. The TZ2 peptide provided a model hairpin system to test the utility of different forms of analysis and isotope labeling patterns for the subsequent study of disordered hairpin peptides. This methodology was next employed to gain insight into the structure of the elastin-like peptide GVGVPGVG, a prototypical disordered system. For this work nine isotopologues were studied in addition to size dependent variants based on the VPGVG sequence and point mutants variants of the form GVGXPGVG. The conformational ensemble was found to contain a high population of irregular P-turns possessing two peptide hydrogen bonds to the proline C=O (see figure below). Further, it was found that this population grows as a function of 1) side-chain volume for the peptide series GVGXPGVG, where X = Gly, Ala, and Val, and 2) polymer size for the peptide series GVG(VPGVG)a, where n = 1-6 and 251. These findings provide new insight into the molecular origin of the mechanical properties of biopolymers containing XPG turns including collagen (X = Pro), elastin (X = Val), mussel byssus (X = Gly), dragline spider silk (X = Gly), and wheat glutenin (X = Gln).` / by Joshua Lessing. / Ph.D.

Thesis: Ph. D. in Biological Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Approximately half of all patients receiving cancer chemotherapy are treated with a platinum-containing drug. Despite this intense clinical use, only three platinum complexes, cisplatin, carboplatin, and oxaliplatin, are approved by the United States Food and Drug Administration for the treatment of cancer. A number of side effects accompany platinum-based therapy and novel approaches are under investigation to attenuate these negative effects and circumvent tumor resistance, be it inherent or acquired. One approach is to use non-classical platinum agents such as platinum(IV) prodrugs and monofunctional platinum(II) complexes. The latter, unlike the classical platinum drugs, can only form one bond to the biological target, DNA. Another strategy is to exploit the advantages offered by nanodelivery. The work presented here spans a range of topics aimed at furthering the development of platinum anticancer therapy along these lines. Fundamental platinum chemistry has been explored to provide ready access to platinum(II) starting materials such as oxaliplatin and mixed ammine/amine platinum(II) complexes. Novel platinum(IV) architectures were uncovered while investigating the oxidative halogenation of cisplatin and carboplatin. Nanoparticle constructs based on the biocompatible amphiphilic block copolymer, PLGA-PEG, have been devised that are capable of delivering both hydrophobic and hydrophilic platinum complexes. Nanoparticle encapsulation has a significant effect on the in vivo properties of the platinum(IV) prodrug mitaplatin. Fundamental studies of the chirality of a potent monofunctional complex, phenanthriplatin, revealed aspects of its interaction with derivatives of the nucleobase guanine, that may have a significant effect on the cellular processing of the DNA adducts formed by this compound. Finally, nanoparticle delivery was used to enhance the ability of phenanthriplatin and phenanthriplatin prodrugs to inhibit the growth of tumors in mice. / by Timothy Charles Johnstone. / Ph. D. in Biological Chemistry

Thesis (B.S.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1940. / MIT copy bound with: Fractional separation of the rare earths by means of the organo-molecular compounds of the anhydrous halides / Arnold Arch. 1940. / Includes bibliographical references (leaf 26). / by Joseph Blackman. / B.S.

Thesis: Ph. D. in Physical Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2018. / Cataloged from PDF version of thesis. Page 257 blank. / Includes bibliographical references. / The far-from-equilibrium dynamics that occur during shock waves cause irreversible material changes that are difficult to measure by conventional techniques. Measuring shocked materials requires techniques that can measure all of the relevant details (pressure, velocity, crystalline phase, etc.) in a single acquisition, or shot. Over the last century, experimental technique development has led to advances in our understanding of how shock waves change and destroy materials. The basic science of the initial shock-induced deformations can allow controlled and effective weapons design for future engineers, if new single-shot techniques can determine how established explosive materials initiate, propagate and detonate. This work focuses on the shock-induced dynamics in explosive 1,3,5-triaza-1,3,5-trinitrocyclohexane (RDX), using new multiobservables techniques and algorithms developed here and elsewhere. RDX has many known crystal phases and decomposition mechanisms, but how shock waves induce decomposition remains poorly understood. With in-situ single-shot X-ray diffraction experiments, we were able to measure the dynamic phase diagram of RDX for the first time, observing a phase transition from the a to y phase at 4 GPa occurs within </_2 ns of the shock front. We saw the lattice of the [alpha]-phase compress isotropically before anisotropically transitioning to the y-phase, foreshadowing the reactivity that is predicted to follow. To study the subsequent mechanical deformations and decomposition chemistry, I extended this work to a waveguide quasi-2D cylindrically converging shock experiment. In-situ measurements demonstrated a strong threshold in shock amplitude at 3 mJ of drive energy, corresponding to a change in the decomposition chemistry, void structures, and deformation planes. Additional findings demonstrated a strongly size-dependent deformation mechanism, indicating interactions between the explosive crystal and the surrounding polymer matrix. These shock-induced deformations clearly intensified when shocked a second time. Together, all of these findings give us a new view of how RDX transforms, deforms, and decomposes within the first 500 ns after a shock wave, giving new insight into hotspots. These RDX studies were enabled by a novel imaging and analysis method. In the quasi-2D cylindrically converging shock geometry, I developed a single-shot imaging technique that collects up to 16 frames with as little as 3ns between frames-3 orders of magnitude faster than existing experiments. This technique enabled us to observe shock propagation and the sequence of stochastic phenomena including in-situ fracture, cavitation,4 phase transitions, and decomposition. To extract quantifiable data and uncertainties with mathematical rigor from our image sequences, I collaboratively developed an image-processing algorithm called locally adaptive discriminant analysis (LADA). LADA reveals boundaries between different features in an image (referred to as classes) using machine learning to sort each pixel of an image into its most probable class. LADA located the shock front in our image sequences, and compiled spatially-resolved ANOVA and MLE values to show uncertainty in the images originating from undifferentiable and outlier pixels, respectively. The multi-frame single-shot imaging technique and LADA method give us a powerful new set of tools to obtain a time sequence of the stochastic chemistry induced by shock waves. These advances in understanding the deformation, the voids and the chemistry in RDX-using our new observational and analysis techniques-lead the way for in-situ studies of decomposition chemistry in RDX. Future work extending the imaging and LADA techniques to X-rays can provide the higher resolution required to determine the timescale and structure of the fracture we saw in our initial experiments. An in-situ version of our ultrasmall-angle diffraction can provide time resolution of the sizes and number densities of the hot-spots, showing the kinetics and extent of local thermal decomposition. Developing a new frequency-resolved class of single-shot Raman experiments could also directly measure the temperature in these hot-spots, experimentally quantifying the activation energy required for thermal runaway to detonation. This work lays the foundation for measurements and experimental techniques that will provide new understanding of how shock waves produce uncontrollable chemistry in explosives. / by Leora Eve Dresselhaus-Cooper. / Ph. D. in Physical Chemistry

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references. / The folding, quality control, and secretion of collagen presents a significant challenge to collagen-producing cells. Each monomeric polypeptide must undergo extensive post-translational modifications, folding and assembly of the C-terminal propeptide globular domain, and isomerization of hundreds of prolyl bonds into the trans conformation before the mature triple helix can form. The triple-helical domain lacks a traditional hydrophobic core that often drives the assembly and folding of globular proteins. Even once folded, the triple helix is at best marginally stable at body temperature and is prone to local regions of unwinding. The process must be highly orchestrated by the endoplasmic reticulum's chaperone network, including maintaining newly synthesized collagen polypeptides in an unfolded, non-aggregated, and unassembled form until after the extreme C-terminus adopts its folded structure. Despite decades of work, however, the mechanisms of collagen folding remain poorly understood, and collagen quality control is largely unexplored. Misfolding collagen variants cause disease, including osteogenesis imperfecta in the case of collagen-I variants. The origins of pathology in osteogenesis imperfecta and the other collagenopathies are still debated, but what is clear is that collagen proteostasis is strongly disrupted. In this thesis, I report a series of studies targeted at elucidating mechanisms of proteostasis for collagen type-1, the most abundant collagen in the human body. First, I explore the folding and assembly of the critically important C-terminal, globular propeptide domains of collagen-I. My data demonstrate the importance of a single amino acid in the globular C-terminal domain that regulates the oligomerization propensity of 30 kDa C-propeptide monomers. Ultimately, I show that this single amino acid guides the assembly of the C-propeptides of all the fibrillar collagens. Second, I use a quantitative mass spectrometry-based interactomics approach and a novel human cell-based model system to map the components of the wild-type collagen-I proteostasis network. This approach resulted in the discovery of > 25 new putative proteostasis mechanisms that engage collagen-I, as well as led to the discovery of a previously unidentified post-translational modification in collagen-I. Finally, I leveraged this improved understanding of the collagen-I proteostasis network to discover a strategy to selectively increase the secretion of collagen-I from primary cells expressing a collagen-I variant that causes osteogenesis imperfecta. Resolving the disease-associated collagen-I secretion defect may prove valuable in disease. / by Andrew Stephen DiChiara. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1988. / Includes bibliographical references. / by Leah Ruby Williams. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1997. / Includes bibliographical references. / by Dana Carise Leard. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2008. / 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. / A number of methodological developments and applications of solid-state NMR for assignment and high resolution structure determination of microcrystalline proteins and amyloid fibrils are presented. Magic angle spinning spectroscopy on uniformly and selectively "C and '5N labeled samples is performed at magnetic fields from 11.7 to 21.1 T and spinning frequencies from 9 to 65 kHz.Dynamic Nuclear Polarization on nanocrystals of amyloidogenic peptide GNNQQNY is presented demonstrating that 'H-'H spin diffusion can efficiently transfer the enhanced polarization across the solute that is not in an intimate contact with the polarizing agent.An improved theoretical treatment of Rotational Resonance Width (R2W) experiments and its application to determination of precise 13C-13C distance is presented. A general theory of second averaging in modulation frame for designing solid-state NMR experiments is introduced and discussed in the context of two methods: Cosine Modulated Rotary Resonance (CMpRR) for performing a broadband double-quantum 13C-13C recoupling without the need for additional 'H decoupling and Cosine Modulated recoupling with Chemical Shift reintroduction (COMICS) that provides a general frequency selective method for measuring precise 13C-13C distances in uniformly labeled solids. Cosine Modulated Adiabatic Recoupling (CMAR) - an adiabatic extension of the CMpRR, that is particularly robust with respect to rf inhomogeneity, is also introduced. A number of applications CMpRR at 21.1 T to proteins with varying degrees of macroscopic order are presented. A second order Third Spin Assisted Recoupling (TSAR) mechanism is introduced and discussed in detail. The heteronuclear TSAR - Proton Assisted Insensitive Nuclei Cross-Polarization (PAIN-CP) and homonuclear Proton Assisted Recoupling (PAR) yield long distance 13C_1-N, 3C-_13C and 15N- 5N restraints in uniformly labeled systems with spinning frequencies up to 65 kHz that are used for protein structure calculation. Structure, dynamics and polymorphism of amyloidogenic peptide GNNQQNY from the yeast protein sup35p are investigated. Finally, PAIN-CP and '3C-13C PAR are used for high resolution de novo structure determination of 10.4 kDa Crh protein dimer. / by Józef Romuald Lewandowski. / Ph.D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1999. / Includes bibliographical references. / This thesis describes the characterization and applications of nanometer sized semiconductor (or quantum dot) colloids produced by chemical means. The nanocrystals are synthesized by pyrolysis of organometallic precursors in the coordinating solvent trioctylphosphine oxide (TOPO). The important developments that have contributed to this method are discussed. Manganese doped CdSe nanocrystals are synthesized using a manganese and selenium containing organometallic compound. Chemical etching and electron paramagnetic resonance (EPR) experiments reveal that most of the dopant atoms lie near the surface within the inorganic lattice. Results from fluorescence line narrowing (FLN) and photoluminescence excitation (PLE) spectroscopies show that doped nanocrystals behave as if they were undoped nanocrystals in an external magnetic field. The nanocrystal surface is initially passivated by dative organic ligands. Better passivation and optical properties are achieved by growth of a large band gap semiconductor shell that provides both a physical and an energetic barrier between the exciton and the surface. (CdSe)ZnS (core)shell are prepared with control over both core and shell sizes. The composite nanocrystals are characterized by absorption, emission, X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), small angle X-ray scattering (SAXS), and wide angle X-ray scattering (W AXS). The maximum quantum yield is achieved when the core is protected from oxidation by a complete shell; thicker shells show no further increase in quantum yield values, due to defects caused by the large lattice mismatch. Exchange of surface TOPO ligands for mercaptocarboxylic acids produces (core)shell nanocrystals that, when treated with base, are soluble in water and remain fluorescent. Established protocols are used to link these water-soluble nanocrystals to the biomolecules avidin or biotin, producing useful fluorescent labels. Stable phosphine tellurides are prepared using hexapropylphosphorus triamide (HPPT). This precursor is used to prepare CdTe nanocrystals that display room temperature quantum yields up to 70%. The CdTe growth is investigated by absorption and emission spectroscopy. CdTe nanocrystals are characterized by TEM and WAXS. / by Frederic Victor Mikulec. / Ph.D.

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