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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Characterization of Spin Coated Polymers in Nano-environments as a Function of Film Thickness

Beck, Catherine Keel 21 August 2001 (has links)
Polymer applications have become more demanding as industry continuously turns to more microscopic parts. Due to the interactions of the polymer chains with the supporting surface and the air interface, the thinner films required for such applications have distinctly different properties than those of the well-defined bulk systems. The goal of the current research is to elucidate the behavior of ultrathin films. Two separate studies were performed on thin films supported on silicon wafer substrates: the first focuses on the viscoelastic cooperativity of thin films, and the second concentrates on the morphological behavior of polymer brush films. For the first study, polymethyl methacrylate films were spin coated onto silicon wafers, and the film thickness was determined using ellipsometry. A series of thin films were examined using techniques such as dielectric analysis and thermal mechanical analysis. The theory of cooperativity, which explains polymeric behavior using the intermolecular and intramolecular forces among polymer chains, was employed to understand the behavior of these thin films. Another type of thin film, a polymer brush, was investigated in the second study. Polymer brushes are formed by chemically bonding one end of many polymer chains to a substrate. The other ends of the chains can interact with the surrounding environment creating a brush-like structure. Constraining one end of a polymer chain alters the behavior of such a thin film. Polymer brushes of the di-block copolymer poly(t-butyl methacrylate) and polystyrene were produced on silicon wafers using spin coating techniques. The effects of both grafting density and solvent washes were analyzed using contact angle analysis and atomic force microscopy. In addition, hydrolysis was successfully performed on existing polymer brush samples to produce polymer brushes of the di-block copolymer polymethyl acrylic acid and polystyrene. / Master of Science
2

Structural and thermodynamic origins of distinct ligand specificity of two homologous PDZ domains

Shepherd, Tyson Robert 01 July 2011 (has links)
Guanine nucleotide exchange factor proteins of the Tiam family are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity. These proteins are modular and contain a variety of interaction domains, including a previously uncharacterized post-synaptic density-95/discs large/zonula occludens-1 (PDZ) domain. Here we report on the structure, specificity, and function of the Tiam1 and Tiam2 PDZ domains. A consensus PDZ-binding motif for Tiam1 was used to predict that two cell adhesion proteins, Syndecan 1 (Sdc1) and Caspr4, are potential Tiam1 PDZ domain binding proteins. Binding interactions were confirmed using fluorescence- and NMR- based binding experiments. The Tiam1 PDZ domain in complex with the C-terminal tails of Sdc1 and phosphorylated Sdc1 were solved using X-ray crystallography. Results showed four residues in two binding pockets in the PDZ domain are important for specificity. Cell biological analysis confirmed the Tiam1/Sdc1 interaction and showed that the PDZ domain has a function in cell-matrix adhesion and cell migration. The four residues deemed important determinants of Tiam1 PDZ domain specificity are not conserved in Tiam2. A combinatorial peptide screen, in combination with biophysical studies, identified a consensus binding sequence for both PDZ domains. Analysis of these consensus sequences and binding assays with peptides derived from native proteins indicated that these two PDZ domains have overlapping but distinct specificities - the Tiam2 PDZ domain was found to bind Caspr4 and neurexin1 but not Sdc1. Additionally, the Tiam2 PDZ domain exhibits significant flexibility in two different regions, a feature not seen in Tiam1. Double-mutant cycle analysis of the four important residues revealed ligand- dependent energetic couplings. Mutating all four residues switched the ligand specificity to that of Tiam2. Analysis of Tiam-family PDZ domain sequences indicated that the PDZ domains segregate into four distinct families based on the residues studied here. A set of "evolved peptides" was used to show the PDZ domain interactions are cooperative throughout the binding pocket in a ligand-specific manner. Collectively, our data suggest that Tiam family proteins have highly evolved PDZ domain/ligand interfaces with distinct specificities and that they have disparate PDZ domain-dependent biological functions.
3

Modulation of the M2 Muscarinic Cholinergic Receptor by Cholesterol

Colozo, Alejandro 18 February 2010 (has links)
M2 muscarinic receptor extracted from Sf9 cells in cholate-NaCl differs from that extracted from porcine sarcolemmal membranes. Whereas the latter has been shown to exhibit non-competitive effects in the binding of N-methylscopolamine (NMS) and quinuclidinylbenzilate (QNB), which can be explained in terms of cooperativity within a receptor that is at least tetravalent, binding to the former is essentially competitive. Levels of cholesterol in Sf9 membranes were only 5% of those in sarcolemmal membranes and were increased to about 100% by means of cholesterol-methyl-β-cyclodextrin. M2 receptors extracted from CHL-treated Sf9 membranes resembled those from heart; that is, cholesterol induced a pronounced heterogeneity detected in the binding of both radioligands, including a shortfall in the apparent capacity for [3H]NMS, and there were marked discrepancies in the apparent affinity of NMS as estimated directly and via the inhibition of [3H]QNB. The data can be described quantitatively in terms of cooperative effects among six or more interacting sites, apparently within an oligomer. Cholesterol also was found to increase the affinity of the receptor for NMS and QNB, and the effect was examined for its possible relationship to the known interconversion of cardiac muscarinic receptors between an agonist-specific (R*) and an antagonist-specific (R) state. Cholesterol and N-ethylmaleimide (NEM) were compared for their effect on the affinity of NMS, QNB and four muscarinic agonists, and the data were assessed in terms of an explicit mechanistic model for a receptor that interconverts spontaneously between two states. The data can be described equally well by an effect of cholesterol on either the distribution of receptors between R and R* or the affinity of all ligands for both states, with an accompanying effect of NEM on either the affinity or the distribution between states, respectively. Since NEM is known from other data to favor R* over R, cholesterol appears to increase affinity per se. Cholesterol therefore is a determinant of affinity and cooperativity in the binding of orthosteric ligands to the M2 receptor. Both effects are observed in solution and therefore appear to arise from a direct interaction between the lipid and the receptor.
4

Modulation of the M2 Muscarinic Cholinergic Receptor by Cholesterol

Colozo, Alejandro 18 February 2010 (has links)
M2 muscarinic receptor extracted from Sf9 cells in cholate-NaCl differs from that extracted from porcine sarcolemmal membranes. Whereas the latter has been shown to exhibit non-competitive effects in the binding of N-methylscopolamine (NMS) and quinuclidinylbenzilate (QNB), which can be explained in terms of cooperativity within a receptor that is at least tetravalent, binding to the former is essentially competitive. Levels of cholesterol in Sf9 membranes were only 5% of those in sarcolemmal membranes and were increased to about 100% by means of cholesterol-methyl-β-cyclodextrin. M2 receptors extracted from CHL-treated Sf9 membranes resembled those from heart; that is, cholesterol induced a pronounced heterogeneity detected in the binding of both radioligands, including a shortfall in the apparent capacity for [3H]NMS, and there were marked discrepancies in the apparent affinity of NMS as estimated directly and via the inhibition of [3H]QNB. The data can be described quantitatively in terms of cooperative effects among six or more interacting sites, apparently within an oligomer. Cholesterol also was found to increase the affinity of the receptor for NMS and QNB, and the effect was examined for its possible relationship to the known interconversion of cardiac muscarinic receptors between an agonist-specific (R*) and an antagonist-specific (R) state. Cholesterol and N-ethylmaleimide (NEM) were compared for their effect on the affinity of NMS, QNB and four muscarinic agonists, and the data were assessed in terms of an explicit mechanistic model for a receptor that interconverts spontaneously between two states. The data can be described equally well by an effect of cholesterol on either the distribution of receptors between R and R* or the affinity of all ligands for both states, with an accompanying effect of NEM on either the affinity or the distribution between states, respectively. Since NEM is known from other data to favor R* over R, cholesterol appears to increase affinity per se. Cholesterol therefore is a determinant of affinity and cooperativity in the binding of orthosteric ligands to the M2 receptor. Both effects are observed in solution and therefore appear to arise from a direct interaction between the lipid and the receptor.
5

PEPTIDOMIMICRY: DESIGN, SYNTHESIS AND CONFORMATIONAL STUDY OF C2-SYMMETRIC OLIGOUREAS

Long, Sihui 01 January 2006 (has links)
Mimicking the structure and even the function of an ??-peptide with artificial chainmolecules such as ??-peptides, ??-peptides and other unnatural oligomers has shown early success.The structural similarities between natural peptides and oligoureas lead to the belief that C2-symmetric oligoureas could be a good candidate for peptidomimicry. Molecular modelingindicates that both homochiral (all monomers have the same absolute configuration) andalternate chiral (absolute configuration of the residues alternate) C2-symmetric oligoureas canform helix- and sheet-like structures in solution conditionally.Several C2-symmetric 1,2-diamines were chosen as the building blocks for the synthesisof chiral oligoureas, and all diamines except for one were prepared in lab. Homochiral andheterochiral oligoureas based on the same diamine or mixed diamines were synthesized in thesolution phase, growing a chain by adding one unit at a time to one terminus or two units at atime to both termini with 4-nitrophenoxycarbonyl (PNP)- activated and t-butoxycarbonyl (Boc)- protected diamines as the intermediates. All the chiral oligoureas were purified by eitherrecrystallization and /or column chromatography and/ or HPLC and characterized by NMR andMALDI-MS. For some oligoureas, crystal structures were obtained. Fragment condensation wasattempted to improve the efficiency of the synthesis, but this approach led to cyclized oligoureasinstead of the desired concatenated residues.Conformational studies of chiral oligoureas were done in both the solid state and thesolution state. The crystal structures of some homochiral oligoureas and some alternate chiraloligoureas indicate that both helix-like structures and extended structures exist for these C2-symmetric oligoureas. NMR and Circular Dichroism (CD) were used to study the conformationof oligoureas in solution, but the conformational study by NMR was not conclusive. CD studyshowed that these oligoureas have multiple conformations in solution and that some of theconformations are sensitive to solvents and temperature. Also, short homochiral and alternatechiral oligoureas based on trans-1,2-diaminocyclohexane (DACH) exhibit signs of cooperativebehavior in solution as gauged by a series of experiments.
6

Hydrogen-bonding and halogen-arene interactions

Dominelli Whiteley, Nicholas January 2017 (has links)
Non-covalent interactions are fundamental to molecular recognition processes that underpin the structure and function of chemical and biological systems. Their study is often difficult due to the interplay of multiple interactions and solvent effects common in complex systems. Herein, chapter one provides some general background on the area before presenting a literature review of key, contemporary developments on the use of folding molecules for the quantification of non-covalent interactions. Chapter two investigates the magnitude and extent of energetic cooperativity in H-bond chains. Utilising supramolecular complexes and synthetic molecular torsion balances, direct measurements of energetic cooperativity are presented in an experimental system in which the geometry and number of H-bonds in a chain were systematically controlled. Strikingly, it was found that adding a second H-bond donor to form a chain can almost double the strength of the terminal H-bond, while further extension had very little effect. Computations provide insights into this strong, short-range cooperative effect in a range of H-bonding contexts. Chapters three and four build on the concepts and molecular models discussed in chapter two. Chapter three discusses the effects of interplay and competition between strong H-bond acceptors such as formyl groups and the weaker organofluorine H-bond acceptor. There has been some debate in recent literature about the latter’s ability to accept H-bonds, the work presented shows that although organofluorine is a weak H-bond acceptor, it can have a significant modulating effect on stronger interactions when in direct competition. Chapter four investigates deuterium isotope effects on conformational equilibria governed by non-covalent interactions. The results show that any deuterium isotope effect which exists is less than the margins of experimental error. Finally, chapter five discusses a molecular torsion balance designed to investigate halogen∙∙∙arene interactions. The interaction energies were investigated in a range of solvents and mixtures in order to dissect out the dispersive and solvophobic components of folding. Overall, these interactions were found to be weak. Nonetheless, a model was used to dissect trends in solvophobic and electronic contributions to the binding using multiple linear regression based upon the cohesive energy density and polarisabilities of the solvents.
7

Protein folding without loops and charges

Kurnik, Martin January 2012 (has links)
Going down the folding funnel, proteins may sample a wide variety of conformations, some being outright detrimental to the organism. Yet, the vast majority of polypeptide molecules avoid such pitfalls. Not only do they reach the native minimum of the energy landscape; they do so via blazingly fast, biased, routes. This specificity and speed is remarkable, as the surrounding solution is filled to the brim with other molecules that could potentially interact with the protein and in doing so stabilise non-native, potentially toxic, conformations. How such incidents are avoided while maintaining native structure and function is not understood.  This doctoral thesis argues that protein structure and function can be separated in the folding code of natural protein sequences by use of multiple partly uncoupled factors that act in a concerted fashion. More specifically, we demonstrate that: i) Evolutionarily conserved functional and regulatory elements can be excised from a present day protein, leaving behind an independently folded protein scaffold. This suggests that the dichotomy between functional and structural elements can be preserved during the course of protein evolution. ii) The ubiquitous charges on soluble protein surfaces are not required for protein folding in biologically relevant timescales, but are critical to intermolecular interaction. Monomer folding can be driven by hydrophobicity and hydrogen bonding alone, while functional and structural intermolecular interaction depends on the relative positions of charges that are not required for the native bias inherent to the folding mechanism. It is possible that such uncoupling reduces the probability of evolutionary clashes between fold and function. Without such a balancing mechanism, functional evolution might pull the carpet from under the feet of structural integrity, and vice versa. These findings have implications for both de novo protein design and the molecular mechanisms behind diseases caused by protein misfolding. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.</p>
8

Binding, Bending and G Jumping in the Minor Groove: Experimental and Theoretical Approaches

Rahimian, Maryam 29 October 2008 (has links)
It has been shown that heterocyclic diamidines, a class of minor groove binders, are promising antimicrobial agents. These compounds bind none covalently to the minor groove of A/T rich regions of the kinetoplast DNA and kill the parasite. The mechanism of action of these compounds is not well understood, yet many hypotheses have been proposed. One of the methods that improve the specificity is cooperative binding. Since there are many binding sites available in k-DNA thus the cooperativity in adjacent binding sites is desirable. A library of compounds has been scanned and few of those compounds identified that are able to bind to two adjacent A/T binding sites separated by a single G. Many biophysical methods such as isothermal titration calorimetry, surface Plasmon resonance, circular dichroism and thermal melting have been used to explore the thermodynamic profiles and binding mode of these compounds. The pulsed field gradient NMR was used to investigate the structural changes to the DNA sequence upon binding of the minor groove binders and find a correlation between their biological difference and structural changes. The molecular dynamics was applied to look at the interaction of some of the heterocyclic diamidines to the DNA with more details and predict the unknown structures.
9

Novel inhibitors of dihydrodipicolinate synthase

2014 January 1900 (has links)
Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step of L-lysine and meso-diaminopimelate biosynthesis, which is the condensation of (S)-aspartate-β-semialdehyde (ASA) and pyruvate into dihydrodipicolinate via an unstable heterocyclic intermediate, (4S)-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinic acid. DHDPS has been an attractive antibiotic target because L-lysine and meso-diaminopimelate are cross-linking components between peptidoglycan heteropolysaccharide chains in bacterial cell walls. Studies revealed that mutant auxotrophs for diaminopimelate undergo lysis in the absence of diaminopimelate in the medium; therefore the assumption is that strong inhibition of DHDPS would result in disruption of meso-diaminopimelate and L-lysine biosynthesis in bacteria and would stop or decrease bacterial growth (eventually leading to bacterial death). In this work, the DHDPS inhibitor design is focused on the allosteric site of the enzyme. It was proposed that a compound mimicking binding of two L-lysine molecules at the allosteric site at the enzyme’s dimer-dimer interface would be a more potent inhibitor than the natural allosteric inhibitor of this enzyme, L-lysine. This inhibitor (R,R-bislysine) was synthesized as a racemic mixture, which was then separated with the aid of chiral HPLC. The mechanism of feedback inhibition of DHDPS from Campylobacter jejuni with its natural allosteric modulator, L-lysine, and its synthetic mimic, R,R-bislysine, is studied in detail. It is found that L-lysine is a partial uncompetitive inhibitor with respect to pyruvate and a partial mixed inhibitor with respect to ASA. R,R-bislysine is a mixed partial inhibitor with respect to pyruvate and a noncompetitive partial inhibitor with respect to ASA, with an inhibition constant of 200 nM. Kinetic evaluation of each DHDPS mutants (Y110F, H56A, H56N, H59A and H59N) has revealed amino acids responsible for the inhibitory effect of L-lysine, R,R-bislysine, and we have found that R,R-bislysine is a strong submicromolar inhibitor of Y110F, H56A, H56N and H59N.
10

Novel Insights Into the Activation of Glycine Receptors

Stephan Alexander Pless Unknown Date (has links)
No description available.

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