Residual dipolar couplings: a complementary tool for stereochemistry determination of drug compounds

NMR-Spektroskopie gehört zu den etabliertesten und leistungsfähigsten Methoden in Chemie und Strukturbiologie, und die Kenntnis der Konstitution, Konfiguration und oft auch der Konformation von Molekülen ist von zentraler Bedeutung für die Entdeckung neuer Wirkstoffe. NMR-Standardparameter wie chemische Verschiebung, 3J-Kopplungskonstanten und NOEs erlauben es, die Mehrzahl der organischen Moleküle strukturell aufzuklären. Verbindungen, die sich einer Strukturaufklärung mit Hilfe dieser Parameter entziehen, lassen sich oft durch Heranziehen komplementärer Parameter wie dipolarer Restkopplungen (RDCs) analysieren. Für die Messung von anisotropen NMR-Parametern werden Orientierungsmedien verwendet wie zum Beispiel mechanisch gespannte Gele, die Anisotropie in der Lösung induzieren. Darüber hinaus sind zur Anpassung der Anisotropie Dehnungsvorrichtungen hilfreich. Für effiziente Messungen von kleinen Probenmengen wurde in dieser Arbeit eine neue Apparatur entwickelt: ausgehend von der vorhandenen 5mm-Dehnungsvorrichtung wurde die Entwicklung einer 3 mm-Dehnungsvorrichtung durchgeführt. Um ebenfalls den Quellschritt des Gels steuern zu können, wurde eine neuartige Quellvorrichtung geschaffen. Die neue Dehnungsvorrichtung wurde in der Praxis getestet und zeigt ermutigende Ergebnisse für die Anpassung der Anisotropie an die passende Stärke. Darüber hinaus wurden Messungen von anisotroper Parametern mit hoher Genauigkeit erreicht. RDCs liefern wertvolle globale-Informationen, zum Beispiel über die Orientierung internuklearer Vektoren innerhalb eines Moleküls. Mit Hilfe von RDCs wurden in der vorliegenden Arbeit die relativen Konfigurationen von Naturstoffen mit mehreren Stereozentren bestimmt, einschließlich der relativen Konfigurationen von tertiären Aminen. Zur Bestimmung der Konfigurationen wurden neben Standardmethoden auch molekular-dynamische Simulationen durchgeführt, in denen experimentelle RDCs als orientierende, tensorielle Randbedingungen verwendet wurden. Die Bestimmung von absoluten Konfigurationen eines Moleküls ist unverzichtbar in der Arzneimittelforschung. Die wichtigste Methode hierzu ist die Röntgenstrukturanalyse, deren Anwendung jedoch durch die Verfügbarkeit eines hochwertigen Kristalls und dem oft hohen Zeitaufwand limitiert ist. Die Entwicklung von weiteren Methoden zur Aufklärung der Stereochemie ist aus diesem Grund ein aktives Forschungsfeld. In dieser Arbeit werden hierzu vorläufige, vielversprechende Daten zur Bestimmung der absoluten Konfiguration von Enantimerenpaare mit Hilfe von RDCs in chiralen Orientierungsmedien präsentiert

50th Rocky Mountain Conference on Analytical Chemistry

Final program, abstracts, and information about the 50th annual meeting of the Rocky Mountain Conference on Analytical Chemistry, co-endorsed by the Colorado Section of the American Chemical Society and the Rocky Mountain Section of the Society for Applied Spectroscopy. Held in Breckenridge, Colorado, July 27-31, 2008

NASA thesaurus. Volume 1: Hierarchical Listing

There are over 17,000 postable terms and nearly 4,000 nonpostable terms approved for use in the NASA scientific and technical information system in the Hierarchical Listing of the NASA Thesaurus. The generic structure is presented for many terms. The broader term and narrower term relationships are shown in an indented fashion that illustrates the generic structure better than the more widely used BT and NT listings. Related terms are generously applied, thus enhancing the usefulness of the Hierarchical Listing. Greater access to the Hierarchical Listing may be achieved with the collateral use of Volume 2 - Access Vocabulary and Volume 3 - Definitions

NASA thesaurus. Volume 2: Access vocabulary

The access vocabulary, which is essentially a permuted index, provides access to any word or number in authorized postable and nonpostable terms. Additional entries include postable and nonpostable terms, other word entries and pseudo-multiword terms that are permutations of words that contain words within words. The access vocabulary contains almost 42,000 entries that give increased access to the hierarchies in Volume 1 - Hierarchical Listing

NASA thesaurus. Volume 2: Access vocabulary

The Access Vocabulary, which is essentially a permuted index, provides access to any word or number in authorized postable and nonpostable terms. Additional entries include postable and nonpostable terms, other word entries, and pseudo-multiword terms that are permutations of words that contain words within words. The Access Vocabulary contains 40,738 entries that give increased access to the hierarchies in Volume 1 - Hierarchical Listing

Biosignature storage in sulfate minerals- synthetic and natural investigations of the jarosite group minerals

The discovery of jarosite on Mars in 2004 generated increased interest in the properties of the mineral related to the search for life on other planets. Several studies indicate that the formation of jarosite can be linked to biological activity on Earth and biomolecules such as amino acids have been found associated with terrestrial jarosite samples. A series of natural and synthetic investigations using different jarosite end-members has been conducted and is presented in this dissertation to investigate the possibility that jarosite can store biosignatures. Natural samples were analyzed by x-ray diffraction, elemental carbon analysis and laser-desorption Fourier transform mass spectrometry (LD-FTMS) and were found to contain the amino acid glycine. Synthetic experiments were conducted in which the different end-members were synthesized in the presence of glycine as well as the amino acid alanine and the amino acid breakdown product methylamine. These samples were analyzed by x-ray diffraction, neutron diffraction, LD-FTMS and thermogravimetric analysis (TGA) techniques. Results of these experiments show that the detection of the biosignature and the effect that biomolecule has on the jarosite minerals is dependent on the end-member and indicate that the jarosite minerals are an excellent target for detecting potential signs of past life on other planets

36th Rocky Mountain Conference on Analytical Chemistry

Program, abstracts, and information about the 36th annual meeting of the Rocky Mountain Conference on Analytical Chemistry, co-sponsored by the Colorado Section of the American Chemical Society and the Rocky Mountain Section of the Society for Applied Spectroscopy. Held in Denver, Colorado, July 31 - August 5, 1994

Diffusion of tin from TEC-8 conductive glass into mesoporous titanium dioxide in dye sensitized solar cells

The photoanode of a dye sensitized solar cell is typically a mesoporous titanium dioxide thin film adhered to a conductive glass plate. In the case of TEC-8 glass, an approximately 500 nm film of tin oxide provides the conductivity of this substrate. During the calcining step of photoanode fabrication, tin diffuses into the titanium dioxide layer. Scanning Electron Microscopy and Electron Dispersion Microscopy are used to analyze quantitatively the diffusion of tin through the photoanode. At temperatures (400 to 600 °C) and times (30 to 90 min) typically employed in the calcinations of titanium dioxide layers for dye sensitized solar cells, tin is observed to diffuse through several micrometers of the photoanode. The transport of tin is reasonably described using Fick\u27s Law of Diffusion through a semi-infinite medium with a fixed tin concentration at the interface. Numerical modeling allows for extraction of mass transport parameters that will be important in assessing the degree to which tin diffusion influences the performance of dye sensitized solar cells

The Dynamics of Folded Nascent Chains Studied With NMR Spectroscopy

Efficient protein folding is vital for biological function. In the cell, this process can begin during biosynthesis, as proteins gradually emerge from the ribosome exit tunnel. Such progressive, co-translational folding of partially synthesised fragments can increase folding efficiency, by reducing the risk of misfolding between adjacent domains. However, the high effective concentration of the ribosome surface itself may potentially also modulate co-translational folding, by forming interactions with the nascent chain which stabilise folded or unfolded states. Solution-state NMR spectroscopy is a uniquely powerful tool to study the conformation and dynamics of the nascent chain beyond the ribosome exit tunnel and probe such effects. The method has previously been applied to characterise the progressive emergence and folding of the FLN5 filamin domain and quantify interactions between the ribosome surface and the unfolded state. However, interactions with folded nascent chains have not so far been studied. As folded states have very different spectroscopic properties to previously studied unfolded states, in this work we sought to develop a toolkit of NMR methods optimised for the analysis of dynamics folded nascent chains. Firstly, we describe the optimisation using mass-spectroscopy of methyl label incorporation into perdeuterated, translationally-arrested ribosome-nascent chain complexes. Secondly, we report the development and application of sensitivityoptimised measurements of relaxation and cross-correlated relaxation in methyl spin systems, which reveal a reduction in the mobility or rotational diffusion of folded FLN5 RNCs. Finally, we combine these approaches with a protein engineering strategy to explore the determinants of folded nascent chain dynamics during translation. We find that mobility increases as translation progresses, but always remains significantly lower than the isolated protein regardless of linker length or composition. We attribute this observation to interactions with the ribosome surface, which we show to be at least partly electrostatic in nature