Copies of author's previously published articles inserted / Describes the exploratory clinical development of tucaresol, consisting of three studies performed on humans and subsequent in vitro and animal studies investigating the possible effects on the immune system. Demostrates that rational drug design may be an efficient way of selecting potential therapeutic candidates. / xxi, 265 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1995

Recent studies of the relationship between protein sequence and protein structure are reviewed. A detailed discussion of past attempts to predict the structure of a protein from its amino acid sequence, the protein folding problem, is presented and the strengths and weaknesses of these methods are examined. The root-mean-square deviation is studied and a benchmark for structural comparisons is established. A combinatorial approach to the protein folding problem is outlined and its advantages over existing methods is discussed. Specific algorithms based on the combinatorial approach are developed and applied to a variety of proteins. The success of this approach in terms of the root-mean-square deviation benchmark as well as the drawbacks of this method are presented.

Previous research has underscored the importance of protein dynamics during light-induced electron transfer; however, specific interactions have not been well characterized. It is of particular importance to understand the role of protein dynamics and cofactor interactions in controlling electron transfer in oxygenic photosynthesis. These factors include hydrogen bonding, ð-stacking and electrostatic interactions. Reaction-induced FT-IR spectroscopy is sensitive to these interactions as well as isotopic incorporation, and is useful to probe protein dynamics associated with light-induced electron transfer in Photosystem I (PSI). Density functional theory (DFT) provides information concerning the vibrational frequencies of molecules as well as the amplitudes of the vibrations and sensitivity to isotope incorporation. Combining these approaches, protein dynamics associated with light-induced electron transfer in PSI were studied. The work presented here describes specific protein cofactor interactions and specific protein relaxation events associated with light-induced electron transfer. The results reported here are consistent with noncovalent protein cofactor interactions that modulate the redox potential of the secondary electron acceptor of PSI. Furthermore, the studies presented here describe novel protein dynamics associated with the oxidation of the terminal electron donor of PSI. These results characterize specific protein dynamics that may be associated with interactions of the soluble electron donors. These studies highlight the importance of protein dynamics in oxygenic photosynthesis.

Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request

Thesis (Ph.D.) -- McMaster University, 1997 / Includes bibliographical references (leaves 151-167) Also available via World Wide Web.

Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

This thesis describes work done with the thyroid hormone receptor (TR), a nuclear protein which binds to specific DNA sequences and regulates transcription in response to thyroid hormone levels. The studies can be divided into two broad categories: structure/function studies of the TR protein, particularly with regards to DNA binding function; and, structure/function studies of the DNA sequences to which the thyroid hormone receptor binds in order to regulate gene transcription. In order to examine the DNA binding properties of the TR an electrophoretic mobility shift assay (EMSA) was utilized. Conditions of this assay were optimized for the use of in vitro translated TR. Mutant forms of the β-isoform of thyroid hormone receptor were generated using a PCR-based mutagenesis protocol. Each mutant substituted a different residue of the 12 amino acid-long α-recognition helix with alanine. The mutants were analyzed for their abilities to bind to thyroid hormone response elements (TREs), and to activate transcription in transfected eukaryotic cells. The DNA binding results were consistent with a conserved α-helix structure, with conserved function for many residues, that is similar to that of the related receptors for glucocorticoids and estrogen. Only the first of the three non-conserved residues lying in the P-box (EGG), a portion of the recognition α-helix that facilitate differential binding of distinct DNA sequences, disrupted binding when substituted with alanine. The third position of the P-box, when substituted with alanine exhibits an altered ability to bind to certain natural TREs. The mutant form of TR with alanine substituted for the second P-box position displayed only a modest decrease in DNA binding affinity compared to wild-type TR (roughly 3-fold), yet was completely deficient in trans-activation. The structure-function studies of TR binding sites on DNA applied a methylation interference protocol to examine the interactions of TR with direct repeats (DR) of the idealized hexameric sequence, spaced by three to five base-pairs. The interactions of both the TR/TR homodimer and the TR/RXR (9-cis-retinoic acid receptor) heterodimer with the DRs were examined. The methylation interference patterns for the TR/TR homodimer bound to the DR sequences are virtually identical for spacers of four and five base-pairs, but with three base-pairs, there is some evidence that at least one DNA binding domain is misaligned with the DNA to accomodate the unfavourable spacer length. The TR/RXR heterodimer methylation interference pattern is distinct on all three DRs, probably due to the fact that in the heterodimer cooperative intermolecular contacts are made between the DNA binding domains of the two receptors, but only when the spacer distance is four base-pairs. When a poorly conserved everted repeat (EvR) that overlaps the idealized DR is present. the homodimer, but not the heterodimer, binds this cryptic EvR in competition with the DR. The binding modality of the TR homodimer and TR/RXR heterodimer to DRs was reevalutated using point mutants and EMSA. The TR homodimer and TR/RXR heterodimer both bind to idealized direct repeats with DBDs aligned appropriately for a direct repeat; however, evidence is presented that there are certain poorly conserved sequences that are intermediate between DRs and EvRs that are differentially recognized by the TR homodimer and the TR/RXR heterodimer. That is, the homodimer binds with the DBDs aligned appropriately for a EvR, and the heterodimer DBDs are aligned appropriately for a DR. / Graduate

Orientadores: Douglas Soares Galvão, Scheila Furtado Braga Llanes / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin / Made available in DSpace on 2018-08-10T15:39:34Z (GMT). No. of bitstreams: 1 Marchiori_MarceloAmorim_M.pdf: 2387821 bytes, checksum: 159d3a99481a5ba6c6eb057065531e6e (MD5) Previous issue date: 2007 / Resumo: A Combretastatina é um estilbeno isolado na década de 80, e vem sendo amplamente estudada pela indústria farmacêutica devido à sua promissora ação anticarcinogênica. Como fármaco anticarcinogênico, age interrompendo o ciclo de polimerização e despolimerização dos microtúbulos, componente celular extremamente importante para a motilidade, manutenção estrutural e mitose celular. Sua principal forma de atuação consiste em despolimerizar os microtúbulos estáveis das células endoteliais da vasculatura tumoral, levando ao bloqueio do fluxo sanguineo que alimenta os tumores cancerígenos. Uma das grandes vantagens da Combretastatina, em relação aos demais medicamentos antineoplásicos, é o fato de não levar à resistência medicamentosa no tratamento quimioterápico. Investigamos a estrutura da Combretastatina e 17 derivados por meio de métodos semiempíricos e estudamos a relação entre as propriedades teóricas e a atividade experimental destes compostos, utilizando três metodologias de reconhecimento de padrões: a Metodologia de Índices Eletrônicos (MIE), a Análise de Componentes Principais (PCA) e a Análise Hierárquica de Clusters (HCA). Para cada metodologia construímos regras e padrões, permitindo a classificação dos compostos em ativos e inativos, a partir das propriedades calculadas teoricamente. Os resultados das três metodologias confirmam a aplicabilidade da MIE e reforçam a importância das variáveis eletrônicas para a classificação da atividade biológica das Combretastatinas / Abstract: Combretastatin, a stilbene isolated in 80's, has been widely studied by the pharmaceutical industry due to its promising anticarcinogenic action. As an antineoplastic agent it acts interrupting the polymerization-depolymerization cycle of the microtubules, an important cellular component to motility, strutuctural maintenance and cellular mitosis. Its main feature consists in dissociate the microtubules in endothelial cells of the tumoral vascular system, leading to disruption of the blood ow that feeds the carcinomas. One of the great advantages of Combretastatin, when compared with others compounds, is the fact that it does not lead to drug resistance in chemotherapy treatments. We investigated the structure of Combretastatin and 17 derivatives using semiempirical methods. We performed the study of the relationship between theoretical properties and experimental activity of these molecules using three pattern recognition methodologies: Electronic Index Methodology (EIM), Principal Component Analysis (PCA) and Hierarchical Clusters Analysis (HCA). For each methodology we found rules and patterns capable of classifying our molecules into active or inactive, using the properties theoretically calculated. The results obtained from the three methodologies confirm the applicability of the EIM and reinforce the importance of the electronic variables for the classi cation of the biological activity of Combretastatins / Mestrado / Estrutura Eletrônica de Atomos e Moleculas / Mestre em Física

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