Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2003. / Includes bibliographical references. / In PART I, the design and the synthesis of planar-chiral phosphaferrocene-oxazolines, a new class of P,N-ligands, are described. The modular nature of their structure allows easy access to a number of analogues in enantiomerically pure forms, facilitating the easy tunability of the chiral environment. These ligands are then applied to several transition metal-catalyzed asymmetric reactions. In Pd-catalyzed asymmetric allylic alkylations, it is established that the planar chirality of the phosphaferrocene, not the central chirality of the oxazoline subunit, is the dominant stereocontrol element. On the other hand, in Cu-catalyzed asymmetric reactions (conjugate additions of diethylzinc to acyclic enones, intramolecular Kinugasa reactions for polycyclic β-lactam synthesis, and [3+2] dipolar cycloadditions of azomethine imines to terminal alkynes), it is demonstrated that the central chirality of the oxazoline subunit is the dominant stereocontrol element, and that the planar chirality of the phosphaferrocene plays a subordinate, although significant, role. In PART II, the enantioselective desymmetrization of cyclic anhydrides and imides by carbon nucleophiles is described. By employing a Grignard reagent/chiral ligand complex as the nucleophile, a range of anhydrides and imides are effectively desymmetrized with uniformly high enantiomeric excess. In these reactions, (-)- sparteine is shown to be the ligand of choice for anhydride substrates, whereas a bisoxazoline is found to be most effective for imide substrates. / by Ryo Shintani. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2014. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references. / Chemical reactions allow biological systems to function. The majority of these biochemical reactions occur due to the work of protein catalysts known as enzymes. These biocatalysts are often thought of as pre-formed, static 'locks' that bind, and subsequently transform, their substrate molecule 'keys'. However, scientists are increasingly finding that dynamic movements of enzymes are a crucial aspect of catalysis. One such example of a system that relies on conformational flexibility is the human DNA repair protein alkyladenine DNA glycosylase (AAG). To efficiently repair DNA, AAG must search the million-fold excess of unmodified DNA bases to find a handful of DNA lesions. Such a search can be facilitated by the ability of glycosylases, like AAG, to interact with DNA using two affinities: a lower-affinity interaction in a searching process, and a higher-affinity interaction for catalytic repair. We have captured crystallographic snapshots of AAG bound to DNA in both high- and lower-affinity states. These depictions reveal several significant and unexpected protein structural rearrangements, providing molecular insight into the DNA-searching process adopted by AAG. By combining these new insights with existing biochemical and structural data, we are able to relate AAG to the big picture question of how DNA binding proteins find their binding sites in the vast expanse of the genome. In another study, a member of a biosynthetic pathway for antibiotic natural products, called kutznerides, was shown to be dependent on conformational changes. The enzyme in question, KtzI, uses a bound flavin cofactor, reducing equivalents from NADPH, and molecular oxygen to install a hydroxyl group on the side-chain nitrogen of the amino acid L-ornithine, which is subsequently incorporated into the kutzneride scaffold. KtzI was structurally characterized after being subjected to various chemical and environmental factors, capturing the enzyme in several states along its catalytic trajectory. These states suggest that a novel conformational change of both the protein backbone and the flavin moiety must take place in order to complete the enzymatic cycle of KtzI. This drastic rearrangement was also shown to be chemically interchangeable in the protein crystal, suggesting that these dynamic motions are catalytically relevant. / by Jeremy Wayne Setser. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1996. / Includes bibliographical references (leaves 258-263). / by Wei Wu. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2007. / Includes bibliographical references. / This thesis summarizes progress toward the ultimate goal of building a complete structural and dynamical model for the CaF molecule. The quantum defects of the Rydberg series of the molecule, as well as their dependences on the internuclear distance and the collision energy of the outer electron, are determined through a quantum defect theory fit of an extensive data set that contains almost all of the electronic states of the molecule that have been observed to date. The result is a global representation of all possible one-electron scattering processes in approximately 90 quantum defect parameters. The utility of such a representation is then demonstrated; the equilibrium quantum defects are used to explore the interaction between electronic and rotational motions in diatomic molecules, and several interesting phenomena are uncovered which would be difficult or impossible to ascertain from a spectrum alone. Nearly all aspects of the interaction between electronic and rotational motion can in fact be understood in classical terms. The thesis concludes with a discussion of ongoing work toward understanding the physical origins of the quantum defects and their dependences on molecular geometry and the electron collision energy. / by Jeffrey J. Kay. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references. / This thesis describes a series of approaches for modeling spectroscopy of molecular systems in aqueous environments, focusing on proton transfer, water dynamics, and hydrogen bonding interactions. The spectroscopy motivating this work ranges from nuclear to vibrational to electronic, spanning from 106 to 1015Hz. The work in this thesis focuses on connecting these spectroscopic measurements directly to the underlying molecular structure through a variety of computational methods. After a discussion of the properties of hydrogen bonds and strongly hydrogen bonded systems, I present a phenomenological approach for modeling linear and nonlinear infrared spectroscopy in condensed phase chemical systems, focusing on applications to strongly hydrogen bonded complexes. In this I also derive and demonstrate the application of a Langevin-like Brownian oscillator model for the bath in computational spectroscopy, utilizing the language of open quantum systems along with the semiclassical approximation for the linear and nonlinear response functions to numerically calculate nonlinear spectra . With this we can examine phenomena previously difficult with other methods, including non-Gaussian dynamics, correlated motions, highly anharmonic potentials, proton transfer, and complex system-bath relationships. Next I describe a design problem reliant on water dynamics and hydrogen bonding: improving and tuning the water enhancement properties of MRI contrast agents. This work focuses specifically on a new ligand architecture with promising modular, tunable synthetic properties. Motivated by the fundamental equations governing relaxivity enhancement, this work proposes systems for which it is possible to improve and tune the molecular rotational timescale, fast water motion, and coordinating water geometry to overcome fundamental limitations in currently available contrast agents. Lastly, this thesis discusses a method of feature selection that works to identify key molecular variables important in influencing the absorption profiles of fluorescent proteins, utilizing machine learning on spectral clusters built from an ensemble of ground state dynamics trajectories. Using the example of green fluorescent protein, I show that this new feature selection protocol can highlight important interactions in the native structure that can help inform rational design of fluorescent proteins. / by Andrew Davis Homing. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1990. / Includes bibliographical references (leaves 67-68). / by Changguo Tang. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, February 2006. / Vita. / Includes bibliographical references (leaves 75-89). / Advances in our understanding of cellular function and signal transduction have resulted in ever increasing number of therapeutical targets and, consequently, underscored a demand for simple and universally applicable markers to monitor activity of the biological system. Gene expression-based screening is based on the assumption that introduction of a compound into biological system would affect directly or indirectly the gene expression, initiating an elaborate expression response to the disturbance of the system. In my thesis work I investigated new strategies to create a limited expression signature accurately representing the activation state of a biological system and to decrease redundancy in the complex expression pattern. To test the validity of our approach, I generated an expression signature for PDGF activation of ERK pathway in human fibroblasts and used this signature to screen a chemical compound library for an inhibitor of PDGFR/ERK pathway. As a result of the screen, I identified aurintricarboxylic acid, ATA, as a new inhibitor of PDGF receptor. The success of this study suggests that endogenous mRNA expression signature is an effective tool to monitor activation state of a cell signaling pathway and can be broadly used to identify compounds modulating condition of a biological system. / by Alena A. Antipova. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2008. / Vita. / Includes bibliographical references. / Energy-dependent proteases, such as the E. coli protease ClpAP, degrade misfolded and short-lived regulatory proteins inside the cell. In this class of proteins, an ATPase component (e.g., ClpA) binds, unfolds, and translocates protein substrates into a protease component (e.g., ClpP) where degradation occurs. This thesis addresses the communication between ClpA and ClpP required to efficiently translocate and degrade protein substrates. Synchrotron hydroxyl radical footprinting is used to show that the ClpA D2 loop, located in the pore of ClpA, is in an "up" conformation when ATP is bound and assumes a "down" conformation when ADP is bound. These results provide the first direct experimental support for a nucleotide-dependent D2 loop conformational change previously proposed to mediate substrate translocation. Synchrotron footprinting also shows that the ClpP N-terminal loops undergo a conformational change, upon the binding of ClpA, from a closed, pore-blocking position, to an open, pore-free position. Complementary kinetic studies show that deletion of the ClpP N-terminus (ClpPAN) accelerates the degradation rate of large peptide substrates 5-15 fold, indicating that opening of the pore is functionally important. Furthermore, unlike ClpAP and wild-type ClpP, ClpPAN shows a distinct slow phase of product formation that is eliminated with the addition of hydroxylamine, suggesting that deletion of the N-terminal loops stabilizes the acyl-enzyme intermediate. Additionally, size-exclusion chromatography and kinetic studies are used to show that ClpP alone can processively degrade a full-length protein substrate in the absence of ClpA, albeit at a 2000-fold slower rate, and furthermore that the size distribution of ClpP-generated peptide products is strikingly similar to the size distribution of ClpAP-generated peptide products. / (cont.)Both distributions contain peaks at integral multiples of 7-8 amino acids, consistent with a mechanism in which ClpP controls product sizes by alternating between translocation in steps of 7-8 amino acids and proteolysis. Collectively, the results presented here indicate that 1) conformational changes in both ClpA and ClpP are necessary for efficient translocation and proteolysis, 2) active site reactivity is linked to conformational changes in the pore region of ClpP, and 3) product sizes are largely controlled by ClpP. / by Laura Danielle Jennings. / Ph.D.

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Chemistry, February 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references. / A tandem benzannulation-cyclization strategy was successfully applied to the synthesis of a tetracyclic heteroaromatic compound expected to have interesting electronic properties. Benzannulation of a diazo ketone and a ynamide yielded a highly substituted aniline that was cyclized to indole according to protocols developed in our laboratory previously. / by Galina Mamaliga. / S.B.

Thesis: S.B. in Chemistry and Biology, Massachusetts Institute of Technology, Department of Chemistry, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 74-79). / Chapter One: Introduction to Type I Collagen and Osteogenesis Imperfecta Collagen-I is the primary proteinaceous component of skin, bone, and tendon. Disruptions in collagen-I homeostasis, typically due to non-synonymous mutations in collagen-- encoding genes, cause a variety of severe incurable diseases, including Osteogenesis Imperfecta (01). 01 phenotypes include brittle, deformed bones, frequent fractures, and growth deficiency. In order to fill the need for treatments that target the underlying causes of collagen-I-related diseases like 01, a better understanding of the collagen-I proteostasis network and how it differentially engages mutant and wild type collagen-1, is required. Chapter Two: Creation and Characterization of a Cell-Based Platform for Delineating the Wild Type and Mutant Collagen-I Proteostasis Network Previous studies of the collagen biosynthetic pathway have been limited by the lack of a biochemically tractable system to allow manipulation of the collagen-I genes (and other genes of interest) and especially by the lack of immunoprecipitation-grade antibodies for collagen-I which has prevented the broad study of the complete set of collagen-1 interacting proteins. We have overcome the challenges of working with the collagen-I genes and have created stable cell lines that inducibly express epitope-tagged versions of both wild type and mutant collagen-1. This platform is greatly facilitating studies of the collagen-I proteostasis network. Chapter Three: Mechanistic Exploration of Novel Collagen-I Interacting Proteins Identified by SILAC Mass Spectrometry Using the model cell platform described in Chapter 2, we have performed an unbiased and quantitative investigation into the network of collagen-I interacting proteins using SILACassisted, quantitative mass spectrometry. The method allowed us to identify more than 25 novel collagen-I interactors. We are currently investigating the mechanistic roles of these proteins in collagen-I processing using shRNA knockdown of proteins of interest. Chapter Four: Creation and Validation of Constructs for the Independent Expression of the Collagen-I C-Propeptide Domains The collagen-I C-propeptide domains are responsible for collagen-I chain selectivity and triple helix nucleation. Many unanswered questions remain relating to the mechanistic details of C-propeptide function both in collagen-I folding and also in diverse biological processes. In order to address these questions, we created and validated constructs that allow the independent expression of the C-propeptide domains. / by Rebecca J. Taylor. / S.B. in Chemistry and Biology