A dissertation submitted in partial fulfilment of the requirements for the degree of Master of Technology: Chemistry, Durban Institute of Technology, 2004. / 4-amino-(D3)-trishomocubane-4-carboxylic acid (tris-amino acid) is a constrained a-amino acid residue that exhibits peculiar conformational characteristics. The aim of the present study is to provide a deeper understanding of these features, which can be used as a guide when chOOSing@shomocubane as suitable building blocks for peptide design. The Ca carbon of@ishomocubane forms part of the cyclic structure, and consequently a peptidic environment was simulated with an acetyl group on its N-terminus and a methyl amide group on its C-terminus. This study involved a complete exploration of the conformational profile of (Yishomocubane using computational techniques.The parm94 parametization of the AMBER oio forc@eld was used to explore the conformational space of the peptide,Q)\xEFshomocubane. The Ramachandran maps computed at the molecular mechanics level' with the parm94 forc@\xEFeld parameters compared reasonably with the corresponding maps computed at the Hartree Fock (HF) level, using the 6-31G* basis set. The results of this study revealed that the conformational profile of the @ishomocubane peptide can be characterized by four low energy regions, viz., C7ax, C7eq, 310 and al helical structures. / M

This thesis presents two contrasting implementations of the optical-feedback cavity-enhanced absorption spectroscopy (OF-CEAS) technique. OF-CEAS com- bines passive optical-feedback locking of semiconductor lasers with cavity-enhanced absorption spectroscopy, and is well suited to sensitive detection of pressure- broadened trace gases. Chapters 1 and 2 set the work in this thesis in context, by describing the theory and discussing the motivations behind trace gas sensing by tuneable laser spectroscopy in the near- and mid-IR. Chapter 3 reviews the theory of OF-CEAS, prior to presenting the results of an experimental implementation based on a near-IR DFB diode laser setup following the traditional V-cavity methodology to spatially decouple the optical- feedback beam from the direct back reflection. The capabilities of the system are demonstrated by accurate determination of a self-broadened half-width at half- maximum of a CO 2 transition, and by detection of acetylene in a car exhaust sample. Chapter 4 describes the design and implementation of the linear cavity method- ology for QCL OF-CEAS, which is the significant contribution of this work. Successful OF-CEAS locking with the linear cavity is shown for two different DFB-QCLs, with close operating wavelengths (5.5 and 5.2 µm) but quite different operating powers and facet size. Chapter 5 presents quantitative spectroscopic results from the linear cavity OF-CEAS instrument, using both lasers. Spec- troscopy on mixes of N 2 O and NO returned sensitivities, quantified by the α min , of 2.7 × 10 −8 cm −1 in 1 s at 0.28 atm and 2.4 × 10 −8 cm −1 in 1 s at 0.19 atm respectively. Limited by etalon fringing on the baseline, the α min compared well with those obtained with V-cavity QCL OF-CEAS instruments. The temporal stability was investigated by Allan variance calculations and the best minimum detectable concentrations for the linear QCL OF-CEAS instrument were 32 ppm for N 2 O (35 s) and 5 ppb for NO (2 s). For NO, this detection limit compares favourably with other mid-IR QCL-based NO sensors, and is sufficient for mon- itoring NO in polluted urban environments. With the Maxion DFB-QCL, mon- itoring of NO in air outside the laboratory was attempted, and an air sample drying system benchmarked. Although this experiment proved unsuccessful, it was possible detect trace amounts of NO desorbing from the walls of the gas cell. Over the course of one hour the concentration rose from 3.8 ± 0.7 ppb to 28.4 ± 0.2 ppb, leading to a rate of desorption of 6.76 ± 0.01 × 10 −3 ppb s −1 . The sensitivity (α min ) of these spectra was 7.0 × 10 −9 cm −1 in 1 s, improved due to the higher mirror reflectivity at the lasing wavelength of the Maxion DFB-QCL, although still limited by etalon fringing.

In this thesis work, the results of microwave investigation and structural determination for benzonitrile and some of its fluorinated derivatives are presented. The pure rotational spectra of the studied compounds including benzonitrile, 2-fluorobenzonitrile, 3-fluorobenzonitrile, 2,3-difluorobenzonitrile, 2,4-difluorobenzonitrile and pentafluorobenzonitrile were investigated. Measuring the rotational spectra of the parent molecules and the minor 13C and 15N isotopic species allowed the derivation of the substitution and effective structures for these molecules. Using the effective and the calculated ab initio structures, the geometries of the fluorinated derivatives were compared to that of the reference compound (benzonitrile) and the effect of single, double and full fluorination on the geometry of benzonitrile was examined. The observed distortions in the BN geometry caused by single, double and full fluorination were interpreted by hybridization theory and intramolecular non-bonded interactions. / February 2015

Thesis (MSc)--University of Stellenbosch, 2006. / ENGLISH ABSTRACT: Quantum mechanics is the method of choice when it comes to the accurate modeling of single molecules and clusters. The correlation energy is the single most important aspect when studying clusters computationally, and reproducing the correlation energy accurately poses a bigger challenge to the computational chemist than in the modeling of single molecules. Very high levels of theory and large basis sets need to be used. Nevertheless, since the calculation of large systems, such as crystals and biological systems, is generally beyond the capacity of quantum mechanics, molecular mechanics is generally used for these systems. Unfortunately due to its nature, molecular mechanics cannot model important quantum effects, but this problem can be solved by a hybrid system in which one part of the system is treated by quantum mechanics and the remaining part by molecular mechanics. In order to combine quantum mechanics with molecular mechanics one needs to optimize the parameters for the molecular mechanics part to allow it to function with the quantum mechanics. The research described in this work is based on the ONIOM-EE method, which is such a hybrid method. In this work we investigate the applicability of the ONIOM-EE method in modeling hydrogen fluoride, carbon monoxide and CO/HF clusters. Most of the clusters’ geometries in this work are not experimentally or computationally known. We therefore perform a computational analysis of all of the clusters by using various methods including Atoms in Molecules, Natural Bond Orbital analysis, Mulliken population analysis and the analysis of delocalized molecular orbitals to obtain information for the development of hybrid systems. During this process we look at different charge derivation schemes and at two different methods of optimizing force field parameters for these clusters. We develop a method to make force field optimization faster and better for specific hybrid systems. This method showed that in all cases the optimized parameters were an improvement on those of the Universal Force Field. We show the importance of an accurate description of the electrostatic interactions in HF, CO and CO/HF clusters and that this is the Achilles heel when attempting to optimize van der Waals parameters for force fields. We further show that atomic point charges are not a good approximation of a molecules’ charge density in hybrid methods. In addition, we make suggestions on how the present method for ONIOM-EE can be improved to make the modeling of van der Waals clusters feasible. / AFRIKAANSE OPSOMMING: Kwantum meganika is die metode van keuse wanneer enkele molekule en molekulêre sisteme op rekenaar gemodeleer moet word. Dit is egter bekend dat die modelering van molekulêre sisteme ’n groter uitdaging stel aan die molekulêre modeleerder, aangesien baie hoë vlakke van teorie en groot basisstelle gebruik moet word om die korrelasie-energie, rekenkundig te produseer. Die akkurate herprodusering van die korrelasie-energie is seker die heel belangrikste vereiste waaraan voldoen moet word as molekulêre sisteme d.m.v. ’n rekenaar gemodeleer word. Nietemin is dit onprakties om kwantum meganiese metodes te gebruik vir groot sisteme soos kristalle of biologiese molekule en juis om dié rede word molekulêre meganika meestal ingespan vir sulke gevalle. Molekulêre meganika is egter ondoeltreffend om belangrike kwantumeffekte te modeleer. Tog is daar ’n oplossing vir hierdie probleem in die vorm van ’n hibried sisteem waar een deel van die sisteem met kwantum meganika en die oorblywende deel van die sisteem met molekulêre meganika behandel word. Om dit moontlik te maak om molekulêre meganika met kwantum meganika te kombineer, moet parameters vir die molekulêre meganika deel geoptimiseer word sodat dit saam met die kwantum meganiese deel kan funksioneer. Die navorsing wat in hierdie studie beskryf word is gebaseer op so ’n hibriedmetode wat bekend staan as ONIOM-EE. In hierdie studie bestudeer ons die moontlikheid om ONIOM-EE te gebruik vir die modelering van molekulêre sisteme van waterstoffluoried, koolstofmonoksied en CO/HF sisteme. Die meeste van die sisteme, wat in hierdie studie behandel word, se strukture is onbekend, beide in terme van eksperimentele gegewens en molekulêre modelering. Ons voer dus ’n volledige analise van al die sisteme uit deur van verskeie metodes soos “Atoms in Molecules”, “Natural Bond Orbital” analise, Mulliken populasie analise en die analise van gedelokaliseerde molekulêre orbitale, gebruik te maak. Dit stel ons in staat om ’n hibriedsisteem te ontwikkel vir die molekulêre sisteme. Gedurende die proses ondersoek ons ook die gebruik van verskillende ladingsafleidings-sisteme en twee metodes word ondersoek waarop ’n kragveld vir ’n hibriedsisteem geoptimiseer kan word. Ons toon aan dat die geoptimiseerde parameters beter resultate lewer as die van die “Universal Force Field” en lig ook die belangrikheid daarvan uit dat die elektrostatiese interaksies se beskrywing ’n hibriedsisteem se Achilles hiel is indien van der Waals parameters geoptimiseer moet word. Ons toon aan dat die gebruik van puntladings op atome om die ladingsdigtheid in molekulêre sisteme te beskryf, ’n onakkurate benadering is. Sekere aanbevelings hoe om die ONIOM-EE metode sodanig te verbeter, dat dit wel gebruik kan word om van der Waals sisteme suksesvol te modeleer, word ook gemaak.

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This dissertation looked at the crystal structure analysis of 2-hydroxymethylpyridine-N-oxide sine this compound could provide data on both substituent effects and hydrogen bonding.

Made available in DSpace on 2015-03-04T18:57:43Z (GMT). No. of bitstreams: 1 thesis_Baptista_LPR.pdf: 17392105 bytes, checksum: cc35fa1188cd3dff14124658b1799f05 (MD5) Previous issue date: 2011-06-29 / A Leishmaniose é uma doença infecciosa causada por protozoários do gênero Leishmania. Segundo a Organização Mundial da Saúde (OMS), cerca de 12 milhões de pessoas estão atualmente infectadas com Leishmaniose. Destes, aproximadamente 90% dos casos ocorrem em países em desenvolvimento, caracterizando-a claramente como uma doença negligenciada. Casos de resistência aos principais medicamentos foram relatados em diferentes países, reafirmando a necessidade de pesquisa e desenvolvimento de novas drogas para o tratamento desta doença. A ribose-5-fosfato isomerase (Rpi), uma importante enzima da via da pentose fosfato, catalisa a interconversão de D-ribose-5-fosfato (R5P) e D-ribulose-5-fosfato (Ru5P). É conhecido que existem dois tipos de Rpi: o tipo B (RpiB) é mais comumente encontrado em procariotos (presente no genoma de Leishmania major) enquanto o tipo A (RpiA) é principalmente encontrado em eucariotos (ausenteno genoma de Leishmania major). Considerando que RpiB não é encontrada em eucariotos superiores, esta enzima pode se tornar um importante alvo para o desenvolvimento de novas drogas antileishmania. Neste trabalho, as estruturas tridimensionais (3D) da Rpi do parasita L. major (LmRpiB) e a RpiA do hospedeiro (Homo sapiens, HsRpiA) foram modeladas usando uma metodologia híbrida combinando modelagem comparativa e ab initio. De posse das estruturas tridimensionais das duas enzimas, foram realizados os seguintes estudos: (i) caracterização e comparação das propriedades físico-químicas dos sítios catalíticos; (ii) validação dos modelos através de estudos de atracamento molecular para predição do modo de ligação de substratos; (iii) estudos de triagem virtual de compostos para determinação de possíveis candidatos a fármacos seletivos. Os resíduos do sítio ativo em ambas as enzimas foram caracterizados quanto ao seu estado de protonação. Os resultados obtidos sugerem que a LmRpiB segue o mecanismos de reação descrito atualmente na literatura. Entretanto, para a enzima HsRpiA foi encontrada uma diferença significativa no estado de protonação do resíduo catalítico Glu182. Foram verificadas diferenças importantes nos volumes de distintos sítios ativos em cada enzima relacionadas a diferenças na acessibilidade ao solvente de resíduos carregados positivamente. Os estudos de atracamento mostraram que em LmRpiB a correta orientação dos substratos _e altamente sensível a variações na posição destes resíduos. Finalmente, ambas estruturas, utilizando os resultados da caracterização dos sítios ativos, foram utilizadas em experimentos de triagem virtual empregando um conjunto de 1202 compostos do banco de ligantes ZINC. Os melhores compostos candidatos a inibidores de LmRpiB foram analisados levando-se em conta a sua seletividade frente a enzima HsRpiA.

Made available in DSpace on 2015-03-04T18:57:48Z (GMT). No. of bitstreams: 1 Dissertacao_Isabella_Final.pdf: 20727738 bytes, checksum: dd3b20329660c2fe2868a6796b23e869 (MD5) Previous issue date: 2011-07-15 / The protein kinases are responsible for regulating various biological mechanisms. The active protein kinase can phosphorylate several substrates and proteins in the body, having an important role in regulating biological functions. The lack of phosphorylation in the process of this family of proteins is associated with various diseases such as cancer, diabetes and rheumatoid arthritis. The human genome contains approximately 478 different kinase genes. Among these, the protein kinases IKK-2 and MAPKp38 are considered potential targets for developing anti-inflammatory drugs. In this work, we used the techniques of comparative modeling and molecular docking for a better understanding of the molecular characteristics and properties which can confer potency and selectivity to the inhibitors described in the literature for these two enzymes. The three-dimensional models built for the IKK's (1 and 2) made possible the understanding of special features available in these enzymes. The study of molecular docking with inhibitors allowed to infer important information about the characteristics of the binding modes that give potency and selectivity to the compounds tested. Regarding MAPKp38, cross-docking studies showed that the conformational change of the A-loop of this enzyme has a profound influence on the results of molecular docking of the inhibitors tested. The success rates of sets of structures of the enzyme were estimated, in order to indicate the combinations of structures that could achieve greater accuracy in real ensemble docking experiments. / As proteínas cinases são responsáveis pela regulação de diversos mecanismos biológicos. A proteína cinase ativa é capaz de fosforilar os substratos e diversas proteínas do organismo, tendo um importante papel na regulação das funções biológicas. O descontrole no processo de fosforilação dessa família de proteínas está associado com diversas doenças, como câncer, diabetes e atrite reumatoide. O genoma humano contém aproximadamente 478 diferentes genes de cinases. Dentre estas, as proteínas cinases IKK-2 e MAPKp38 são consideradas como potenciais alvos para o desenvolvimento de fármacos anti-inflamatórios. Neste trabalho, foram utilizadas as técnicas de modelagem comparativa e atracamento molecular para obter um melhor entendimento das características e propriedades moleculares que podem conferir potência e seletividade aos inibidores descritos na literatura para estas duas enzimas. Os modelos tridimensionais construídos para as IKK s (1 e 2) tornaram possível o entendimento de características especiais existentes nessas enzimas. O estudo de atracamento molecular de inibidores possibilitou inferir informações importantes com relação às características dos modos de ligação que conferem potência e seletividade aos compostos testados. Com relação à MAPKp38, os estudos de crossdocking demonstraram que a variação conformacional do A-loop desta enzima exerce grande influência nos resultados de atracamento molecular em inibidores potentes. Conjuntos de estruturas da enzima tiveram as taxas de sucesso estimadas, com o objetivo de indicar as combinações de estruturas que poderiam obter a maior acurácia em experimentos reais de ensemble docking.