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Womack, James Christopher. "Evaluating many-electron molecular integrals for quantum chemistry." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.687429.
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The evaluation of molecular integrals is a vital but computationally expensive part of electronic structure calculations. This computational expense is particularly problematic for the explicitly correlated methods, in which complicated and numerous integrals over more than two-electrons must be evaluated. The successful R12/F12 methods overcome this difficulty by decomposition of these many-electron integrals by means of approximate resolutions of the identity (RIs). To obtain accurate results with this approach, however, requires large auxiliary basis sets with high angular momentum functions. To address this issue, we present a new RI-free variant of MP2-F12 theory, which uses density fitting to approximate three-electron integrals, rather than RIs. This approach demonstrates improved convergence of calculated energies with respect to the size and maximum angular momentum of the auxiliary basis set compared to the standard RI-based approach. For the systems on which the method was tested, relatively small auxiliary basis sets were sufficient to reduce errors in the correlation energy to less than a millihartree. The software implementation of the three-electron integral types needed in the new MP2-F12 variant proved to be extremely time-consuming. This difficulty inspired us to develop "Intception", a code generator which generates code for molecular integral evaluation. Intception is capable of automatically implementing code for evaluating a wide range of molecular integral types, using a general theoretical framework based on Obara-Saika-type recurrence relations [1] . To flexibly express integral definitions for use in Intception, a new domain-specific language was created. Testing revealed that the generated code evaluated integrals to a high numerical accuracy and on a reasonable timescale, though somewhat slower than existing optimized implementations. A detailed analysis of the performance of the generated code was undertaken, which suggested some possible routes to improving the efficiency of the code.
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Jensen, Daniel S. "Real-Space Approach to Time Dependent Current Density Functional Theory." BYU ScholarsArchive, 2010. https://scholarsarchive.byu.edu/etd/2559.
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A real-space time-domain calculation of the frequency-dependent dielectric constant of nonmetallic crystals is outlined and the integrals required for this calculation are computed. The outline is based on time dependent current density functional theory and is partially implemented in the ab initio density functional theory FIREBALL program. The addition of a vector potential to the Hamiltonian of the system is discussed as well as the need to include the current density in addition to the particle density. The derivation of gradient integrals within a localized atomic-like orbital basis is presented for use in constructing the current density. Due to the generality of the derivation we also give the derivation of the kinetic energy, dipole, and overlap interactions.
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Sturdy, Yvette Katherine. "Molecular simulation with path integral methods." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436950.
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Righi, Assis Francisco Moro. "Calculo de orbitais moleculares na molecula LiH e no ion BeH+ com tratamento algebrico das integrais." reponame:Repositório Institucional da UFSC, 1998. http://repositorio.ufsc.br/xmlui/handle/123456789/77784.
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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciencias Fisicas e MatematicasMade available in DSpace on 2012-10-17T07:28:34Z (GMT). No. of bitstreams: 0Bitstream added on 2016-01-09T00:26:07Z : No. of bitstreams: 1 109966.pdf: 2204184 bytes, checksum: 21712f4f2c8eabccd377dde54704284a (MD5)
Técnicas de computação algébrica são utilizadas na resolução de integrais que aparecem no estudo de moléculas diatômicas. Soluções analíticas são obtidas para integrais de um e de dois centros híbridas e de Coulomb com orbitais atômicos do tipo de Slater (STO). Tratamento semelhante é usado no estudo das integrais de troca. Usando estes resultados, propriedades eletrônicas, como distância internuclear de equilíbrio e momento de dipolo, do estado fundamental da molécula LiH e do íon BeH+ são investigadas fazendo-se um cálculo variacional com uma base de orbitais moleculares. O comportamento das cargas efetivas dos orbitais atômicos é estudado em função da distância internuclear. A influência de um campo elétrico externo bastante intenso na ligação química é um fenômeno pouco discutido teoricamente. Neste trabalho, o comportamento das curvas de energia potencial da molécula LiH e do íon BeH+ em campo externo uniforme também é investigado. Os efeitos na dissociação molecular são analisados.
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Newport, Thomas. "Tools and resources for molecular simulations of integral membrane proteins." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:b6dc3047-aaf4-4236-8266-7a885fecb5d9.
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Integral Membrane Proteins (IMPs) are an important and scientifically interesting class of protein which span the lipid bilayer surrounding cells, cell compartments and many viruses. Molecular Dynamics (MD) simulation has revealed intimate and often highly specific relationships between membrane lipids and IMPs critical to many metabolic and signalling pathways. Meanwhile, the use of Coarse-Grained (CG) MD techniques has extended capabilities of biomolecular simulation to larger proteins over longer time periods. Several tools and resources for biomolecular simulations of IMPs are presented here, as well as two MD studies of specific IMPs. The previously developed MemProtMD pipeline automates the setup of MD simulations of IMPs; major extensions to this are presented here with the MemProtMD database and web server, automating the analysis of IMP simulations. The results of this can be viewed using the MemProtMD web server, an interactive, searchable online resource containing data from simulations of over 3000 experimentally determined IMP structures in explicit lipid bilayers. Using data from analysis of the entire MemProtMD database, MemProtMetrics has been developed to automate identification and orientation of IMP structures from Protein DataBank (PDB) depositions. This is shown to effectively predict membrane protein orientations seen in MD simulations. A tool for identification and classification of membrane lipids is also described, and used to identify over 500 IMPs structures with resolved lipids. CGMD simulations have also been used to assess dependence on side-chain ionisation state of interactions between lipids and two IMPs observed in mass spectrometry experiments. The simulations reveal similar trends to those seen in experiments. Finally, using multi-scale simulations, and through the development of a novel method for altering membrane composition in MD simulations, lipid-specific scramblase activity was shown for a novel structure of the TMEM16K scramblase IMP.
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Kasahara, Kento. "Integral Equation Theories of Diffusion and Solvation for Molecular Liquids." Kyoto University, 2018. http://hdl.handle.net/2433/232056.
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Silveira, Rodrigo Leandro 1986. "Aspectos moleculares da degradação de biomassa lignocelulósica : dinâmica de enzimas e nanoarquitetura de paredes celulares de plantas." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/248864.
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Orientador: Munir Salomão SkafTese (doutorado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: A produção de bioetanol a partir da biomassa lignocelulósica integra processos físico-químicos e enzimáticos que comprometem sua viabilidade econômica. A biomassa possui uma estrutura recalcitrante composta de celulose, hemicelulose e lignina. Tal estrutura, bem como os mecanismos das enzimas, não são bem compreendidos. Nesta tese, simulações de dinâmica molecular e a teoria mecânico-estatística 3D-RISM foram utilizada para investigar aspectos moleculares da degradação de biomassa, incluindo: (1) dinâmica estrutural de celulases; (2) base molecular da termofilicidade de laminarinaes; (3) disrupção não-hidrolítica de biomassa por expansinas; (4) nanoarquitetura da parede ceular primária; e (5) forças termodinâmicas da parede celular secundária. No tópico (1), observou-se que a acessibilidade ao substrato em celulases pode ser modulada por alterações na estrutura primária, com consequências para a atividade enzimática. Observou-se também que a inibição por produto está relacionada a alterações conformacionais de resíduos próximos ao sítio de ligação. Adicionalmente, alterações na dinâmica intrínseca das enzimas ocorrem conforme a etapa do processo de hidrólise. No tópico (2), os resultados mostraram que a conformação do sítio de ligação ao substrato de laminarinases é sensível a variações de temperatura. No tópico (3), observou-se que a expansina pode transladar sobre a superfície da celulose e induzir torções em cadeias de glucano, sugerindo a possibilidade de romper ligações de hidrogênio celulose-celulose e/ou celulose/xiloglucano como um zíper. No tópico (4), observou-se que a agregação de nanofibrilas de celulose se dá através de suas faces hidrofílicas e que a presença de hemicelulose estabiliza tal agregação. No tópico (5), os resultados mostraram que as forças de coesão da parede celular secundária são de natureza entrópica e que a composição química da lignina modula as interações lignina-lignina e lignina-hemicelulose
Abstract: Biofuel production from lignocellulosic biomass involves physico-chemical and enzymatic processes that challenge its economic viability. The lignocellulosic biomass is recalcitrant against degradation and is made up of cellulose, hemicellulose and lignin. This structure and the enzyme mechanisms are not fully understood. In this thesis, molecular dynamics simulations and the statistical mechanical theory 3D-RISM were employed to assess molecular aspects of the biomass degradation, including: (1) structural dynamics of cellulases; (2) molecular basis of the thermophilicity of laminarinases; (3) non-hydrolytic disruption of biomass by expansins; (4) primary cell wall nanoarchitecture; and (5) thermodynamic forces of the secondary cell wall. In the topic (1), we observed that cellulase substrate accessibility can be modulated through changes in its primary structure, with consequences to the enzymatic activity. Moreover, the product inhibition is related to conformational changes of residues located close to the substrate binding site. In addition, changes of the intrinsic dynamics allow cellulases change their function according to the hydrolysis step. In the topic (2), we show that the substrate binding site conformation of laminarinases is sensitive to temperature variations. In the topic (3), we observed that the expansin can translade over the cellulose surface and induce torsions in free glucan chains, suggesting the possibility of disruption of cellulose-cellulose and cellulose-xyloglucan hydrogen bonds as a ziper. In the topic (4), the results showed that the aggregation of cellulose nanofibrils takes place through their hydrophilic face and that hemicellulose plays roles in stabilizing such aggregation. In the topic (5), we observed that the cohesion forces within the secondary cell wall are of entropic origin and that the lignin chemical composition modulates the lignin-lignin and lignin-hemicellulose interactions
Doutorado
Físico-Química
Doutor em Ciências
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Spura, Thomas [Verfasser]. "Ab initio path integral molecular dynamics : theory and applications / Thomas Spura." Paderborn : Universitätsbibliothek, 2015. http://d-nb.info/1078666504/34.
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Niegowski, Damian. "Structural biology of integral membrane proteins from methods to molecular mechanisms /." Doctoral thesis, Stockholm : Department of Biochemistry and Biophysics, Stockholm Univeristy, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-30069.
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Phan, Isabelle Q. H. "Structural studies of modular proteins by NMR and molecular modelling." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294330.
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Greenhalgh, Stephen Nicholas. "Cellular and molecular mechanisms of liver regeneration." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28846.
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Improved understanding of how the liver regenerates would be of great value, particularly given the dearth of therapies for end-stage liver disease. Currently, the only effective treatment for total liver failure is transplantation. Such an invasive, costly and specialised intervention is unable to address the enormous global impact from diseases of the liver. Ironically, the liver has the greatest regenerative potential of any organ in the mammalian body. However, this capacity for repair is overwhelmed in the face of massive or repeated injury. Understanding the key factors driving or inhibiting successful liver regeneration offers the potential for novel, targeted therapies to promote regeneration of a patient’s own liver. Animal models are widely used when studying complex, dynamic, multicellular processes such as liver injury and regeneration. Continued progress in transgenic modification of mice, combined with ongoing advances in microscopy techniques, means that the opportunity now exists to observe labelled cells, and subcellular structures, in real time and in vivo, with previously unobtainable resolution and fidelity. Not only does this afford the opportunity for novel insights into both normal physiology and the response to injury or disease, it can vastly expand the amount of biologically relevant information that can be obtained from each experimental animal. Hence, it is possible to advance scientific knowledge and reduce experimental animal use simultaneously. This thesis examines the role of αv integrins in liver regeneration. Integrins are expressed on the surface of cells and can perform a range of functions, including signalling and extracellular matrix adhesion. The most well-characterised role for αv integrins is activation of transforming growth factor beta, a molecule which has been shown to inhibit hepatocyte proliferation and liver regeneration. Partial hepatectomy was used as an experimental model of liver injury and regeneration. It was performed in mice, in which one or more αv integrins had been genetically depleted from specific cell types in the liver, namely hepatocytes, hepatic stellate cells or liver sinusoidal endothelial cells. These investigations revealed that depletion of integrin αvβ8 from hepatocytes led to increased hepatocyte proliferation and accelerated liver regeneration. The possible mechanisms through which hepatocyte integrin αvβ8 may exert its braking effect on liver regeneration following injury were also explored. In parallel, a novel experimental system to permit intravital multiphoton microscopy of the regenerating liver following partial hepatectomy in mice was developed and validated. Intravital imaging of mouse liver was performed with a range of cellular labels, combined with a fluorescent cell cycle reporter and label-free imaging modalities. This demonstrated the enormous potential of the system to study the dynamics of hepatocytes and non-parenchymal cells in the regenerative niche, reconstruct the sinusoidal vascular network in three dimensions during angiogenesis, and measure sinusoidal blood flow and parenchymal lipid deposition. Advances in experimental animal models such as this drive forward our understanding of the cellular and molecular mechanisms of liver regeneration whilst refining and reducing experimental animal use. Novel insights into the process of liver regeneration will permit the development of innovative therapeutic strategies to allow this remarkable organ to heal itself even in the face of massive or sustained insult.
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More, Joshua N. "Algorithms and computer code for ab initio path integral molecular dynamics simulations." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:b8ca7471-21e3-4240-95b1-8775e5d6c08f.
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This thesis presents i-PI, a new path integral molecular dynamics code designed to capture nuclear quantum effects in ab initio electronic structure calculations of condensed phase systems. This software has an implementation of estimators used to calculate a wide range of static and dynamical properties and of state-of-the-art techniques used to increase the computational efficiency of path integral simulations. i-PI has been designed in a highly modular fashion, to ensure that it is as simple as possible to develop and implement new algorithms to keep up with the research frontier, and so that users can take maximum advantage of the numerous electronic structure programs which are freely available without needing to rewrite large amounts of code. Among the functionality of the i-PI code is a novel integrator for constant pressure dynamics, which is used to investigate the properties of liquid water at 750 K and 10 GPa, and efficient estimators for the calculation of single particle momentum distri- butions, which are used to study the properties of solid and liquid ammonia. These show respectively that i-PI can be used to make predictions about systems which are both difficult to study experimentally and highly non-classical in nature, and that it can illustrate the relative advantages and disadvantages of different theoretical methods and their ability to reproduce experimental data.
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Arora, Rohit. "Molecular mechanism of HIV-1 integrase inhibition by Raltegravir proposed by using of molecular modeling approaches." Phd thesis, École normale supérieure de Cachan - ENS Cachan, 2012. http://tel.archives-ouvertes.fr/tel-00905951.
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The HIV-1 integrase catalyzes the integration of HIV-1 viral DNA (vDNA) into the host cell chromosome in a process, which is essential for viral replication through two independent reactions, 3'-processing (3'-P) and strand transfer (ST), catalyzed by IN. Deciphering the structural determinants of the interaction between integrase and its substrates and the kinetics of this interaction sheds light on the importance of inhibitors targeting the pre-integration IN*vDNA complex. This approach led to the identification of raltegravir (RAL) and elvitegravir (ELV), which turned out to be highly efficient inhibitors of ST. RAL, formerly known under the code MK-0518, is a new anti-HIV drug that obtained clinical approval in the United States under the name IsentressTM on October 12, 2007. ELV is still in clinical trials. However, these compounds nevertheless encounter resistance phenomenon. To date, no experimental data characterizing the RAL structure, structure of the HIV-1 IN and/or interactions of RAL with its targets, has been reported.First, we characterized the structural and conformational properties of RAL in different states ‒ the gas phase, in water solution and the solid state. Second, a detailed study allowed characterisation the RAL recognition by the viral targets ‒ IN and the vDNA, before and after the 3'-P. We found that RAL shows a broad spectrum of conformations and configurations in isolated state and/or associated with the target(s). The best docking poses and scores confirmed that the model representing IN*vDNA complex is a biologically relevant target of RAL. This result is consistent with the commonly accepted mechanism of RAL inhibition.Based on the docking results we suggested that the inhibition process may include, as a first step, the RAL recognition by the processed vDNA bound to a transient intermediate IN state. RAL coupled to vDNA shows an outside orientation of all oxygen atoms, excellent putative chelating agents of Mg2+ cations, which could facilitate the insertion of RAL into the active site. The conformational flexibility of RAL further allows the accommodation/adaptation of the inhibitor in a relatively large binding pocket of IN*vDNA pre-integration complex thus producing various RAL conformation. We believe that such variety of the RAL conformations contributing alternatively to the enzyme residue recognition may impact the selection of the clinically observed alternative resistance pathways to the drug.We also studied the recognition of the HIV-1 IN inhibitors from two different strains, B and CRF02_AG. Our in silico study showed that the sequence variations between CRF02_AG and B strains did not lead to any notable difference in the structural features of the enzyme and did not impact the susceptibility to the IN inhibitors. Our analysis of the resistance mutations effects showed that structure of the wild-type enzyme and mutants is almost identical. However, the resistance mutations significantly altered the specificity of the viral DNA recognition by IN.We performed molecular dynamics simulations of the native and mutated IN with a point mutation R228A localized in the C-terminal domain. The study of targets flexibility opens a very promising way, not only in terms of fundamental research, but also for the application of our concepts to the development of new generations of inhibitors targeting IN.
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Ivanov, Sergei. "Path Integral studies of quantum systems at finite temperatures." Doctoral thesis, Stockholm : Division of Physical Chemistry, Arrhenius Laboratory, Stockholm University, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-628.
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Agarwal, Animesh [Verfasser]. "Path Integral Techniques in Molecular Dynamics Simulations of Open Boundary Systems / Animesh Agarwal." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1114735221/34.
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Oliveira, Heibbe Cristhian B. de. "Um procedimento analítico para o cálculo das integrais bi-eletrônicas em métodos de mecânica quântica molecular." reponame:Repositório Institucional da UnB, 2008. http://repositorio.unb.br/handle/10482/6462.
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Tese (doutorado)—Universidade de Brasília, Faculdade de Química, Departamento de Nutrição, 2008.Submitted by Larissa Ferreira dos Angelos (ferreirangelos@gmail.com) on 2009-09-09T19:27:13Z No. of bitstreams: 1 2008_HeibeCristhianBenditoOliveira.pdf: 7244812 bytes, checksum: a34df7739bc6420c53ceacb6e390d605 (MD5)
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Neste trabalho desenvolvemos uma metodologia alternativa (método das q-Integrais) para o cálculo de integrais de dois-elétrons em métodos ab initio de mecânica quântica molecular. O método das q-Integrais é baseado na função q-Exponencial, a qual provém da mecânica estatística não-extensiva de Tsallis. A vantagem deste procedimento é que o tempo de CPU para o cálculo de integrais de dois-elétrons é substancialmente reduzido quando comparado com as metodologias usuais. Para validar esta nova metodologia, o método das q-Integrais foi aplicado em quatro situações usando os níveis de cálculo Hartree-Fock, MP2 e CC (aproximações CCD e CCSD): i) gerar as curvas de energia potencial dos sistemas moleculares H2, N2, O2, F2 e HF utilizando conjuntos de funções de base STO-3G, STO- 6G, Slater (base mínima) e double-zeta(DZV), considerando várias distâncias interatômicas entre 0; 5 e 8; 0 bohr; ii) calcular as constantes espectroscópicas e o espectro rovibracional para os sistemas moleculares relatados; iii) otimizar a distância interatômica dos referidos sistemas moleculares; iv) calcular o momento de dipolo (para sistemas heteronucleares), a polarizabilidade linear estática e a segunda hiperpolarizabilidade em funcão da distância interatômica usando duas diferentes metodologias: métodos Hartree-Fock Acoplado(CPHF) e Campo Finito (FF). Nossos resultados estão em bom acordo com os obtidos utilizando os procedimentos usuais para cálculo de integrais de dois-elétrons, indicando claramente que o método das q Integrais é acurado o bastante para ser usado em cálculos mecânico-quânticos moleculares. O método das q-Integrais foi implementado no código fonte do programa geral de química quântica GAMESS. ______________________________________________________________________________ ABSTRACT
The present work develops an alternative methodology (q-Integral method) to evaluate the two-electron integrals which appear in ab initio molecular quantum mechanical calculations. The q-Integral method is based on the q-Exponential function, which comes from the Tsallis non-extensive statistics mechanics. The advantage of this procedure is that the CPU time for calculating the two-electron integrals is substantially reduced when compared with the usual methods. To validate this new methodology, the q Integral method was applied in four cases using the Hartree-Fock, MP2 and CC (CCD and CCSD approaches) theory: i) to build up the potential energy curves of the molecular systems H2, N2, O2, F2 and HF using the STO-3G, STO-6G, Slater (minimal basis) and double-zeta (DZV) atomic basis sets, assuming several interatomic distances varying between 0.5 and 8.0 bohr; ii) to evaluate the spectroscopic constants and the rovibrational spectra for the related molecular systems; iii) to optimize the interatomic distance of the related molecular systems; iv) to calculate the bond length dependence of the dipole moment (to heteronuclear systems), static linear polarizability and second hyperpolarizability via two different approaches: the Coupled Hartree-Fock (CPHF) and Field Finite (FF) methods. Our results are in good agreement with those obtained through the standard procedure for calculating the two-electron integrals, implying that the q-Integral method is accurate enough to be used in any molecular quantum mechanical calculation. The q-Integral method was implemented in the source code of the general ab initio quantum chemistry package GAMESS.
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Melo, Eduardo Borges de. "Estudos teoricos (modelagem molecular e QSAR) de inibidores de HIV-1 integrase." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/248539.
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Orientador: Marcia Miguel Castro FerreiraTese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica
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Resumo: Apesar da implantação da HAART, existe uma necessidade contínua de novos agentes anti- HIV. Os inibidores da enzima HIV-1 integrase (HIV-IN) constituem um dos mais recentes avanços na luta conta a AIDS. A principal abordagem utilizada nessas pesquisas são os métodos relacionados ao planejamento de fármacos auxiliados por computador (CADD). Neste trabalho, foram realizados três estudos QSAR (2D, 4D e híbrido) utilizando um conjunto de treinamento formado por 85 compostos descritos como inibidores da reação de transferência de fita catalisada pela HIV-IN. No estudo QSAR-2D, foram utilizados 1291 descritores físico-químicos obtidos por diversos programas. Para o estudo QSAR-4D, perfis de amostragem conformacionais (PACs) foram obtidos com o programa de dinâmica molecular Gromacs 4, e 65.856 descritores de campo (Coulomb e Lennard-Jones) foram obtidos a partir do programa LQTA-QSAR. As seleções de variáveis foram realizadas pela metodologia Ordered Predictors Selection (OPS), e os modelos foram construídos utilizando regressão por quadrados mínimos parciais (PLS). Na etapa de QSAR-2D, foi realizado um estudo preliminar com 33 compostos com baixa variabilidade estrutural e 167 descritores de mais simples interpretação. O modelo obtido foi formado por duas variáveis latentes e quatro descritores. Esse modelo apresentou uma relação direta com o mecanismo de inibição mais aceito. Já para o modelo com o conjunto completo, foram selecionados quatro descritores, porém de difícil interpretação, provavelmente devido à grande variabilidade estrutural do conjunto de treinamento. Já para o modelo QSAR-4D, uma relação direta com o mecanismo de inibição, com descritores correspondentes à interação com os co-fatores metálicos e com a alça hidrofóbica do sítio de ligação da HIV-IN, também pôde ser traçada. Todos os modelos apresentaram qualidade estatística aceitável, com boas capacidades de predição interna e robustez, além de não apresentarem correlação ao acaso. Já o modelo híbrido, construído com alguns dos descritores selecionados nos estudos anteriores, possui alta qualidade estatística, mas é inferior ao modelo QSAR-4D. Logo, ao serem considerados os resultados obtidos, conclui-se que os objetivos da tese foram alcançados e que os modelos obtidos apresentaram grande potencial para proposição de novos inibidores da HIV-IN.
Abstract: Despite the HAART implantation, there is a continuous need to search for new anti-HIV agents. The HIV-1 integrase (HIV-IN) inhibitors are one of the most recent breakthrough in AIDS research. So, the computer aides-drug design (CADD) related methods have been the main approach used in the research of such class of drugs. In this work, three QSAR studies (2D, 4D and hybrid), with a training set, consisted of 85 inhibitors of strand transfer (ST) reaction catalyzed by HIV-IN. In the 2D-QSAR study, 1,291 physicochemical descriptors were obtained by several programs. For the 4D-QSAR study, the conformational essembles profiles (CEPs) were obtained by the molecular dynamic program Gromacs 4. With the LQTA-QSAR program, 65,856 descriptors (Coulomb and Lennard-Jones) were obtained. In both the studies, the variable selections were carried out according to the Ordered Predictors Selection (OPS) method while the models were composed with Partial Least Squares (PLS) regression. In the 2D-QSAR step, a preliminary study with 33 compounds with low structural variability and 167 descriptors of more simple interpretation was developed. The obtained model was based on two latent variables and four descriptors. But, for the model with a complete set, there were four selected descriptors, although the difficult interpretation, probably due to the great structural variability of the training set. On the other hand, a direct relation with the inhibition mechanism could be traced for the 4D-QSAR model, including descriptors related with the interaction with the metallic co-factors and with the hydrophobic loop, placed in the binding site of HIV-IN. All the models showed an acceptable statistic quality, with good capacity of internal prediction and robustness. Moreover, the models did not present any randomized correlation. But, the hybrid model, built with some of descriptors selected in both studies, although it also has high statistic quality, is inferior to the 4D-QSAR model. Hence, considering the good obtained results, it can be concluded that the purposes of this thesis were achieved and that the models present a great potential to propose new HIV-IN inhibitors.
Doutorado
Físico-Química
Doutor em Ciências
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Huang, Shuai. "Efficient and Accurate Path Integral Simulations of Thermochemical Properties." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/28051.
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The accurate calculation of quantum thermochemical properties is a challenge for contemporary computational chemistry. Path integral Monte Carlo (PIMC) simulations provide an efficient and scalable method to estimate full-dimensional properties in large chemical systems. In this thesis, we investigate different implementations of PIMC simulations and combine them with the modified Shepard interpolation (MSI) of molecular potential energy surfaces (PESs). We demonstrate these methods can be made accurate and efficient for bound state molecular systems.
Within the path integral formalism, we consider the primitive approximation of the action and three higher order approximations: Takahashi-Imada, Suzuki-Chin and Chin. The resulting PIMC methods are benchmarked using spectroscopically accurate PESs for water and HCN–HNC and parameters within the Suzuki-Chin and Chin approximations are numerically optimised. The Suzuki-Chin approximation is shown to provide the most computationally efficient PIMC simulations.
The accuracy of the PIMC method relies on the quality of molecular PES. A review of the GROW procedure for molecular PESs, and its underlying MSI, is undertaken. Our PIMC code is incorporated within GROW software suite, allowing new PES configurations to be chosen from path integral sampling of configuration space at a given temperature. This allows PESs to be automatically and iteratively improved from a small set of initial molecular configurations. We apply the GROW procedure to methane, as a prototypical bound state system, using the numerically optimised Suzuki-Chin action, to determine thermochemical properties. These calculations allow efficient strategies for choosing initial configurations for bound state problems to be developed and the dependence of quantum thermochemical properties on electronic structure method and basis set to be determined.
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Polo, André Sarto. "Sistemas químicos integrados via complexos de rênio(I) e rutênio(II) na conversão de energia." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/46/46134/tde-26042007-112045/.
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O trabalho desenvolvido teve como foco dois sistemas químicos integrados: células solares sensibilizadas por corantes, Dye-Cells®, e fotossensores baseados em compostos de rênio(I). Novos compostos de rutênio(II) foram preparados, caracterizados e investigados como corantes sensibilizadores. Os resultados obtidos com as células solares sensibilizadas pelo cis-[(H3BCN)2Ru(dcbH2)2], H3BCN- = cianoboroidreto, dcbH2 = ácido-4,4\'-dicarboxílico-2,2\'-bipiridina, são: Jsc = 8,0 mA.cm-2, Voc = 0,66 V, Pmax = 2,7 mA.cm-2 e ff = 0,51. Esse dispositivo atingiu eficiência de conversão de fótons incidentes em corrente de até 23%. Os compostos cis-[Ru(dobH2)2(L)2]0/2+, dobH2 = ácido-4,4\'diidroxâmico-2,2\'-bipiridina e L = Cl-, H2O ou NCS-, foram preparados usando o ácido hidroxâmico como um novo grupo de ancoramento. Os desempenhos das células solares são: cis-[(Cl)2Ru(dobH2)2]: Jsc = 4,6 mA.cm-2, Voc = 0,60 V, Pmax = 1,4 mW.cm-2, ff = 0,51; cis-[Ru(dobH2)2(H2O)2]2+: Jsc = 4,4 mA.cm-2, Voc = 0,61 V, Pmax = 1,6 mW.cm-2, ff = 0,59; cis-[(SCN)2Ru(dobH2)2]: Jsc = 4,6 mA.cm-2, Voc = 0,71 V, Pmax = 1,5 mW.cm-2, ff = 0,46. A similaridade dos valores de Jsc sugere que o grupo de ancoramento pode estar limitando o processo de injeção de carga na banda de condução do semicondutor. Frutos distintos dos já investigados são utilizados como fontes de antocianinas empregadas como sensibilizadores. Esses corantes naturais são capazes de adsorver à superfície do semicondutor e realizar a conversão de luz em eletricidade. Foram determinados eficiência de conversão de fóton incidente em corrente de até 19% e valores de Jsc = 7,2 mA.cm-2, Voc = 0,65 V, Pmax = 2,0 mW.cm-2 e ff = 0,55. O segundo sistema químico integrado investigado baseia-se em fotossensores com fac-[Re(CO)3(NN)(stpy)]+, NN = 2,2\'-bipiridina, bpy, 4,4\'-dimetil-2,2\'-bipiridina, Me2bpy, ou dipirido[3,2-a:2\',3\'-c]fenazina, dppz, stpy = trans ou cis-4-estirilpiridina. A reação de isomerização trans-cis do ligante coordenado pode ser acompanhada de duas formas distintas por espectrofotometria e por ressonância magnética nuclear, 1H RMN. Os rendimentos quânticos aparentes, Φap, determinados para irradiação em 404 nm, por espectrofotometria, são: fac-[Re(CO)3(bpy)(trans-stpy)]+ Φap = 0,19 ± 0,02; fac-[Re(CO)3(Me2bpy)(trans-stpy)]+ Φap = 0,18 ± 0,02; fac-[Re(CO)3(dppz)(trans-stpy)]+ Φap = 0,30 ± 0,03. Enquanto os valores reais determinados por 1H RMN, Φreal, são: fac-[Re(CO)3(bpy)(trans-stpy)]+ Φreal = 0,48 ± 0,03; fac-[Re(CO)3(Me2bpy)(trans-stpy)]+ Φreal = 0,31 ± 0,07; fac-[Re(CO)3(dppz)(trans-stpy)]+ Φreal = 0,48 ± 0,06. Os valores determinados por 1H RMN são reais uma vez que os sinais do produto e do reagente são detectados em regiões distintas, o que não acontece no acompanhamento por espectrofotometria. A isomerização trans-cis do composto fac-[Re(CO)3(bpy)(trans-stpy)]+ também é observada em poli(metacrilato) de metila, que foi o meio rígido utilizado visando o desenvolvimento de dispositivos. O isômero fac-[Re(CO)3(bpy)(cis-stpy)]+ é luminescente e a sua emissão é investigada em diferentes meios analisando os deslocamentos hipsocrômicos com o aumento da rigidez do meio.The focus of this work is on two chemical integrated systems: dye-sensitized solar cells, Dye-Cells®, and photosensors based on rhenium(I) compounds. Novel ruthenium(II) compounds were synthesized, characterized and investigated as dye-sensitizers. The results of solar cells sensitized by cis-[(H3BCN)2Ru(dcbH2)2], H3BCN- = cyanoborohydride, dcbH2 = acid-4,4\'-dicarboxylic-2,2\'-bipyridine, are: Jsc = 8.0 mA.cm-2, Voc = 0.66 V, Pmax = 2.7 mA.cm-2 and ff = 0.51. Incident photon-to-current efficiency of up to 23% is achieved by this device. The cis-[Ru(dobH2)2(L)2]0/2+ compounds, dobH2 = acid-4,4\'-dihydroxamic-2,2\'-bipyridine, L = Cl-, H2O or NCS-, were synthesized using hydroxamic acid as a new anchoring group. The performance of these dye-sensitized solar cells are: cis-[(Cl)2Ru(dobH2)2]: Jsc = 4.6 mA.cm-2, Voc = 0.60 V, Pmax = 1.4 mW.cm-2, ff = 0.51; cis-[Ru(dobH2)2(H2O)2]2+: Jsc = 4.4 mA.cm-2, Voc = 0.61 V, Pmax = 1.6 mW.cm-2, ff = 0.59; cis-[(SCN)2Ru(dobH2)2]: Jsc = 4.6 mA.cm-2, Voc = 0.71 V, Pmax = 1.5 mW.cm-2, ff = 0.46. The similarity between Jsc values suggests that the anchoring group is limiting the electron injection into the semiconductor conducting band. Anthocyanins of several fruits were employed as sensitizers. These natural dyes are capable of adsorbing onto the semiconductor surface and promote the light-to-electricity conversion. Incident photon-to-current efficiency of up to 19% and values Jsc = 7.2 mA.cm-2, Voc = 0.65 V, Pmax = 2.0 mW.cm-2, ff = 0.55 were determined. The second chemical integrated system investigated is based on photosensors using fac-[Re(CO)3(NN)(stpy)]+, NN = 2,2\'-bipyridine, bpy, 4,4\'-dimethyl-2,2\'-bipyridine, Me2 bpy, or dipyrido[3,2-a:2\',3\'-c]phenazine, dppz, stpy = trans or cis-4-styrylpyridine. The trans-cis isomerization of the coordinated ligand is followed by two distinct ways, spectrophotometry and nuclear magnetic resonance, 1H NMR. The apparent quantum yields, fiap, determined for irradiation at 404 nm by spectrophotometry are: fac-[Re(CO)3(bpy)(trans-stpy)]+ Φap = 0.19 ± 0.02; fac-[Re(CO)3(Me2bpy)(trans-stpy)]+ Φap = 0.18 ± 0.02; fac-[Re(CO)3(dppz)(trans-stpy)]+ Φap = 0.30 ± 0.03. The real values, Φreal, determined by 1H NMR, are: fac-[Re(CO)3(bpy)(trans-stpy)]+ Φreal = 0.48 ± 0.03; fac-[Re(CO)3(Me2bpy)(trans-stpy)]+ Φreal = 0.31 ± 0.07; fac-[Re(CO)3(dppz)(trans-stpy)]+ Φreal = 0.48 ± 0.06. The values determined by 1H NMR are real since the signals of the product and of the reactant are detected in distinct regions, which does not occur for the spectrophotometric method. The trans-cis isomerization of the compound fac-[Re(CO)3(bpy)(trans-stpy)]+ is also observed in poly(methyl)methacrilate, which was the rigid medium employed aiming the development of devices. The fac-[Re(CO)3(bpy)(cis-stpy)]+ isomer is luminescent and its emission is investigated in different media analyzing the hypsochromic shifts increasing the rigidity of the medium.
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Iqbal, Sarah. "Molecular studies of stiff skin-causing mutations in fibrillin-1." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:c23ac97b-dbf3-44b3-9e56-7a860038519e.
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Fibrillin-1 is the main component of the 10-12 nm microfibrils, which are found in several elastic and non-elastic tissues. Human fibrillin-1 contains multiple calcium-binding epidermal growth factor-like (cbEGF) domains interspersed with transforming growth factor β-binding protein-like (TB) domains. TB4 domain contains a flexible RGD loop which mediates cell adhesion via αVβ3, α5β1 and αVβ6 integrins. Mutations which introduce amino acid substitutions into TB4 are associated with a wide spectrum of diseases such as Marfan syndrome (MFS), ectopia lentis, Stiff skin syndrome (SSS). Amino acid substitutions such as W1570C, C1564S and C1577G in the TB4 domain have been found to cause SSS. The upstream TB5 domain has been predicted to modulate integrin binding and a deletion in the domain has been found in Weill-Marchesani syndrome (WMS), phenotype of which is similar to SSS (skin fibrosis and short stature), thereby suggesting that the underlying pathogenic mechanism might be similar. This study has used cellular, biochemical and biophysical methods to investigate the effects of SSS substitutions C1564S and W1570C on domain structure and function and compared it to a MFS substitution C1564Y in the TB4 domain and WMS deletion in the TB5 domain. Effects of the SSS mutations on structure of the domains were studied using limited proteolysis, nuclear magnetic resonance spectroscopy and calcium chelation experiments. Subsequently, the ability of human fibroblasts to secrete wild-type and mutant fibrillin-1 was examined to identify the effect of the mutations on the trafficking of the protein. Finally, cell binding assays and SPR was employed to investigate the effect of disease-causing mutations on fibrillin-1/integrin interactions. The results demonstrate that the SSS mutations affect TB4-cbEGF23 interface and calcium-binding to cbEGF23 but do not alter secretion of recombinant fibrillin-1 mutant fragments from the cell. On the other hand, intracellular retention was observed for MFS substitution C1564Y which was shown to be more susceptible to proteolysis than SSS substitution C1564S. WMS deletion also gives rise to partial retention of the recombinant fragment, suggesting a different pathogenic mechanism for these disorders. Cell binding assays and surface plasmon resonance (SPR) experiments show that SSS mutations affect binding to αvβ3 integrin, but not αvβ6 integrin suggesting that selectively impaired integrin interactions may contribute to pathogenesis of SSS.
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Hazelbaker, Dane. "Structural elements that influence lambda integrase interactions within higher-order complexes executing site-specific recombination." View abstract/electronic edition; access limited to Brown University users, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3318325.
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Amavisca, Edward D. 1965. "Electron(hole)-phonon interaction in YBCO high temperature superconductor using quantum path integral molecular dynamics." Thesis, The University of Arizona, 1991. http://hdl.handle.net/10150/277899.
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In this research, we have implemented an original technique to study the electronic properties of a single electron placed in YBa2 at 300K. Using a discretized extension of Feynman's Quantum Path Integral, we have been able to characterize effective electron-phonon interactions, and electron location site probability. We find that the electron stabilizes at oxygen vacant sites in the copper-oxygen chains. In the copper-oxygen planes, the electron is unstable and moves into the chain. Upon complementing the quantum electron to a positive charge thereby simulating a hole, we then find that the hole moves into favorable sites in the copper-oxygen planes. These sites are surrounded by four oxygens and two copper ions. Next, by decoupling the electron and hole from the lattice, we obtain effective electron-phonon and hole-phonon coupling constants on the order of 30. These results indicate that the next area of research is to move toward a multi-electron system and allow for further study of the electrons near the Fermi level. Some of the difficulties associated with multi-electron systems such as "exchange", are briefly discussed.
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Hoyte, Ashley Christopher. "Molecular Mechanisms for Antiviral Activities and HIV-1 Resistance to Allosteric Integrase Inhibitors." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1543436136541123.
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VILELA, Marinalda Anselmo. "Caracterização molecular de isolados bacterianos apresentando mecanismos de resistência a antimicrobianos que atuam na parede celular." Universidade Federal de Pernambuco, 2009. https://repositorio.ufpe.br/handle/123456789/6180.
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Previous issue date: 2009O objetivo desse estudo foi caracterizar bactérias causadoras de infecção hospitalar que apresentam resistência aos dois principais grupos de antibióticos que afetam a síntese da parede celular representados pelos glicopeptídeos e ß-lactâmicos. Neste, reportamos o isolamento e caracterização das primeiras amostras de Enterococcus faecalis resistentes ao glicopeptideo vancomicina (VRE) no Nordeste do Brasil e isolados clínicos de Klebsiella pneumoniae resistentes aos antibióticos ß-lactâmicos envolvidos em episódios de infecções hospitalar. Estes isolados foram testados quanto a susceptibilidade aos antimicrobianos de escolha. Os enterococos foram tipificados por meio de macro-restrição do DNA cromossomal e analisados quanto a presença dos genes de resistência e de elementos genéticos móveis. Os isolados apresentaram resistência a múltiplos antimicrobianos e apenas um perfil genético foi encontrado, sugerindo a disseminação de uma linhagem clonal entre os pacientes infectados, também a presença específica do gene vanA e do elemento de transposição Tn1546-like associado a plasmídios mostram capacidade de disseminação dos mecanismos de resistência aos glicopeptídeos por meio de processos de conjugação genética entre as bactérias. Os isolados de K. pneumoniae foram tipificados por ribotipagem e analisados quanto a presença dos genes de resistência e de elementos genéticos móveis. Os isolados apresentaram o fenótipo de ESBL, ou seja, produtoras de ß-lactamases de espectro ampliado. Este fenótipo foi associado a presença dos genes blaTEM, blaCTX-M e blaSHV tanto no cromossomo como em plasmídios naturais dos isolados. Estes genes foram detectados em diferentes associações, como genes únicos (25,5%), duplos (41,8%) e triplos (32,7%). A presença dos três genes no mesmo isolado foi detectada em percentuais superiores àqueles relatados na literatura. Em adição, foram também detectadas as presenças do integron de classe 1 carreando outros genes de resistência, gerando o fenótipo de co-resistência dessas bactérias a outros antimicrobianos. A detecção de várias linhagens clonais mostra o surgimento de vários eventos de resistência ou a transferência dos marcadores genéticos entre as bactérias. Assim, os resultados puderam mostrar o crescimento da disseminação dos elementos genéticos de resistência bacteriana a antibióticos entre isolados de bactérias causadoras de infecção hospitalar, diminuindo, assim, as possibilidades terapêuticas para o tratamento dessas infecções
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Poma, Bernaola Adolfo Máximo. "La energía libre de un sistema cuántico vista a través de las integrales de camino de Feynman." Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2013. https://hdl.handle.net/20.500.12672/4311.
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La idea principal de esta tesis es describir en forma compacta los principios físicos involucrados en el cálculo de propiedades termodinámicas, por ejemplo la energía libre, en sistemas cuánticos a través del formalismo de las integrales de camino de Feynman aplicado a la Dinámica Molecular Ab Initio. Un método ampliamente usado en el estudio de propiedades electrónicas de sistemas condensados. Para este fin esta tesis consiste de cuatro capítulos:
El primero trata los fundamentos de la dinámica molecular ab initio. La cual yace sobre la aproximación adiabática de Born-Oppenheimer. Se presenta la Teoría del Funcional de la Densidad como uno de los métodos optimizados para el cálculo de las fuerzas (de carácter electrónico) sobre los núcleos atómicos en el estado fundamental (T = 0).
El segundo discute el formalismo de integrales de camino de Feynman. El cual abre la posibilidad de incluir efectos cuánticos a temperatura finita (T > 0). Se describe el isomorfismo clásico de la función de partición cuántica a través de las integrales de camino. Por último, discutimos la implementacion numérica de este formalismo y sus limitaciones.
El tercero trata una de las limitaciones de la dinámica molecular ab initio: los llamados eventos raros. Se muestra como un tratamiento clásico del problema con ayuda de las integrales de camino consigue mejorar el muestreo de eventos y asi facilita el cálculo de la energía libre entre estados (meta)estables.
En el cuarto se aplica el formalismo descrito en el capítulo anterior para la reconstrucción cuántica de la energía libre en el caso de la tranferencia de un protón en una molécula de malonaldehido.
Por último, presentamos las conclusiones de esta tesis.Tesis
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Antonellis, Patrick Joseph. "Acf7 is a Hair-Bundle Antecedent, Positioned to Integrate Cuticular Plate Actin and Somatic Tubulin." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1365110648.
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Lee, Chong Yong. "Electron-phonon interaction in barium-potassium-bismuth-oxygen superconductor by quantum path integral molecular dynamics (QPIMD)." Diss., The University of Arizona, 1990. http://hdl.handle.net/10150/185239.
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We have introduced two different techniques in this paper to investigate the high Tc superconductor BaK BiO₃. The first one is the rigid-ion molecular dynamics model to calculate classical properties of the crystal. This method provides the ionic anisotropic vibrational spectra. It is found that the oxygen modes dominate the vibrational spectrum from 150 cm⁻¹ up to 820 cm⁻¹. An increase in the number of substituted K around an oxygen favors high frequency vibrational modes. We have also determined by experiment IR spectrum. The absorption peaks are between 380 to 880 cm⁻¹. Our experimental and computational data are in good agreement in the high frequency region. The second technique used to investigate this high Tc superconductor is based on a quantum path integral molecular dynamics. It has been applied for the first time to the determination of electron-phonon interaction energy. We estimate the electron phonon coupling constant at about 1.34. This value represents a weak to moderate electron-phonon coupling in Ba₁₋ₓKₓBiO₃ in agreement with current views of this pairing mechanism in this material.
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Iyer, Venkatraman 1967. "Discretized path integral molecular dynamic simulations with quantum exchange of two electrons in molten potassium chloride." Thesis, The University of Arizona, 1992. http://hdl.handle.net/10150/278142.
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This study presents the use of Feynman's Quantum Path Integral (QPI) approach in the Molecular Dynamic Simulation of two electrons in molten KCl. In this research, we have successfully implemented an original technique to tackle the questions of spin dependent quantum exchange phenomenon between two electrons. It was found that two electrons with antiparallel spins form a stable bipolaronic complex and those with parallel spins repel each other and form two dissociated or singlet states. Calculations of the average energies compare well with previous computational findings by Selloni et al. who used a direct integration of the time dependent Schrodinger equation. The radial distribution function illustrated clearly that the triplet state nests itself among the cations, namely K+. The electron-electron separation distance was found to be ∼3.5 A for the triplet state and the singlet case showed the electrons being repelled as far as possible; namely half the size of the simulation cell ∼7 A.
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Gardiner, Brooke Bridget Anne. "Molecular changes defining the transition from radial to vertical growth phase in melanoma /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19280.pdf.
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Chakraborty, Arup R. "Differential expression of integrin [alpha]₃[beta]₁ and [alpha]₆[beta]₄ molecules on a panel of rat esophageal cell lines." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=bgsu1131345357.
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Silva, Adilson José da. "Vacinas recombinantes contra erisipela suína: desenvolvimento integrado de bioprocesso, da biologia molecular ao biorreator." Universidade Federal de São Carlos, 2011. https://repositorio.ufscar.br/handle/ufscar/255.
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Previous issue date: 2011-10-11Valée S.A.
Swine erysipelas is among the diseases that causes great economic losses in swine cultures worldwide. The disease is caused by the bacterium Erysipelothrix rhusiopathiae, and the surface protein SpaA is one of its main antigens. Herein, we report studies concerning the development of recombinant vaccines against swine erysipelas based on the SpaA antigen. Protein production for a subunit vaccine formulation was studied in shaken flasks and 5.0 L bioreactors. For this propose, a 1026 bp fragment of the spaA gene was cloned in Escherichia coli cells under the lac promoter control. The recombinant organism (E. coli BL21(DE3) pET28a_spaA) was cultivated in fed batch using complex medium with glycerol as carbon source. Nonconventional induction strategies were evaluated and high protein yield (198 mgprot/gDCW) and productivity values (0.4 gprot/L.h) were reached. The same antigen was cloned for expression and secretion in attenuated Salmonella typhimurium cells to obtain a live bacterial vector for the SpaA antigen. The recombinant lineage was able to express and secrete the SpaA fragment fused to the alpha-hemolysin secretion signal both in vitro and in vivo. High plasmid maintenance was observed in both conditions. The vaccinal vehicle showed to be able to colonize the Peyer patches and to invade the gut epithelial barrier in the inoculated animals. Immunization tests in murine model showed that the recombinant antigen delivered by Salmonella cells inoculated by oral route induced the production of seric IgG antibodies anti-SpaA. According to the literature, these antibodies must be able to promote pathogen opsonization in case of infection, contributing to confer a protective immunity against swine erysipelas to the vaccinated animals. In summary, this work presents contributions to development of subunit vaccines against swine erysipelas, in the form of recombinant protein formulations, or SpaA antigen delivery by attenuated S. typhimurium cells.
A erisipela suína é uma das enfermidades que causam grandes prejuízos na suinocultura em todo o mundo. A doença é causada pela bactéria Erysipelothrix rhusiopathiae, e a proteína de superfície SpaA desse microrganismo é um de seus principais antígenos. Neste trabalho, estudou-se o desenvolvimento de vacinas recombinantes contra a erisipela suína a partir do antígeno SpaA. Avaliou-se a produção de uma vacina de subunidade composta pelo antígeno recombinante, a qual foi estudada em frascos agitados e em biorretores de bancada de 5,0 L. Para isso, um fragmento de 1026 pb do gene spaA foi clonado em células de Escherichia coli sob controle do promotor lac e o organismo recombinante (E. coli BL21(DE3) pET28a_spaA) foi cultivado em batelada alimentada, utilizando-se meio complexo contendo glicerol como fonte de carbono. Estratégias não convencionais de indução foram avaliadas e altos valores de rendimento (198 mgprot/gDCW) e produtividade (0,4 gprot/L.h) da proteína recombinante foram alcançados. O mesmo antígeno foi clonado em um plasmídeo que possibilita a expressão e secreção da proteína recombinante em Salmonella typhimurium atenuada, a fim de se obter um vetor bacteriano vivo para o antígeno em questão. A linhagem recombinante foi capaz de expressar e secretar o fragmento da proteína SpaA fusionado ao sinal de secreção da alfa-hemolisina tanto in vitro quanto in vivo, apresentando alta taxa de manutenção plasmidial nas duas condições. Além disso, o veículo vacinal se mostrou capaz de colonizar as placas de Peyer e de invadir a barreira epitelial do intestino dos animais inoculados. Ensaios de imunização em modelo murino mostraram que a veiculação do antígeno pelas células de Salmonella inoculadas por via oral induziu a produção de anticorpos IgG séricos anti-SpaA, que de acordo com a literatura, devem ser capazes de promover a opsonização do patógeno em caso de infecção, contribuindo para conferir uma imunidade protetora contra a erisipela suína aos animais vacinados. Em suma, este trabalho apresenta contribuições para o desenvolvimento de vacinas de subunidade contra a erisipela suína na forma de uma vacina de proteína recombinante, ou por veiculação do antígeno SpaA por linhagens atenuadas de S. typhimurium.
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Mohaisen, M. R. "Molecular characterization of the activity and requirements of a novel and promiscuous bacteriophage integrase." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3011837/.
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Stx bacteriophages are responsible for the dissemination and production of Shiga toxin genes (stx) across the Shigatoxigenic E. coli (STEC). These toxigenic bacteriophage hosts can cause severe, life-threatening illness, and Shiga toxin (Stx) is responsible for the severe nature of EHEC infection, a subset of pathogenic STEC. At the point of Stx phage infection, the injected phage DNA can direct its integration into the bacterial chromosome becoming a prophage; the host cell is then known as a lysogen. Unusually, our model Stx phage, Φ24B, can integrate into at least four distinct sites within the E. coli genome that shared no easily identifiable recognition sequence pattern. The identification of what are actually required for phage and bacterial DNAs recombination has been tested using both in vitro and in situ recombination assays. These assays enabled the simple manipulation of bacterial attachment site (attB) and phage attachment site (attP) sequences. The aim of the study is to fully characterize the requirements of this promiscuous integrase, carried by the Stx phage Φ24B (IntΦ24B), to drive integration. These assays enabled us to identify the minimal necessary flanking sequences for attB site identified (21 bp and 49 bp from the right and left the cross over region, respectively) and the attP site (200 bp each side). Furthermore, we identified that the Φ24B integrase does not need Integration Host Factor (IHF) to drive integration. Finally, as this integrase can integrate the phage genome inside at least four different bacterial attachment sites (attBs), these sites were identified, sequenced and cloned in different compatible plasmids to be transformed to one cell, and the frequency and preference of each recombination were tested by means of qPCR. The results showed, the recombination with secondary attachment sites was less frequent than that with the primary site. Furthermore, within five minutes, there was also a preference of site, as recombination occurred in both attB1 and attB2, while recombination with the attB4 and attB3 sites, took 1 hour and 2 hours, respectively.
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Sarmento, Felipe José de Queiroz. "Desenvolvimento de uma plataforma de bioinformática integrada aplicada a identificação molecular de microrganismos patogênicos." Universidade Federal da Paraíba, 2013. http://tede.biblioteca.ufpb.br:8080/handle/tede/9943.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
Various researches in molecular epidemiology, molecular diagnosis and evolutionary genetics related to pathogens are compared to managing large amounts of data derived from institutions such as, hospitals or laboratories. Although there already are some proposals to connect molecular information to the diagnosis of pathogens, none of them uses high performance bioinformatics tools which are embedded in a system and linked to a patient’s electronic record. The MolEpi tool has been developed as a system of data and information management addressed to public health, incorporating clinical and epidemiological information about patients, as well as molecular data of 16S rRNA sequences of pathogenic bacteria. In order to confirm which species of these bacteria were identified, biological samples (urine, secretions and purulent wounds, tracheal aspirate and blood) and subsequently incubation and growth of colonies in culture, and PCR was used followed by sequencing and analysis of the conserved coding region for 16S ribosomal RNA (rDNA). Such strategy enabled fast bacterial identification, regardless of prior knowledge of the species of microorganism under study. Moreover MolEpi is a system interconnected to repositories of specific sequences as Genbank (NCBI), RDP-II (Ribosomal Database Project - MSU) and GreenGene (LBL). In this way, once the sequences of clinical isolates are confirmed and validated, they can be used as reference in the identification of other unknown microorganisms. Thus, a local database was established, representing the profile of pathogens found in the hospital unity of study and which should be object of public health surveillance. In order to develop MolEpi, we used the Java programming language and the PostgreSQL8.3 object-relational database. It was also developed BACSearch, which has the following programs to handle the analysis of 16S rDNA sequences, we used the framework BioJava; to multiple alignment, ClustalW2, MAFFT and MUSCLE, and for editing of multiple alignment and phylogenetic analysis, the JalView2.4.0 was used. The system was validated with 200 clinical specimens isolated and identified from sites of nosocomial infection. The DNA sequences produced from these samples were subjected to BLAST by using the developed tool, which identified Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Morganella morganii as the main pathogens involved. Data on resistance patterns of the species were obtained in microbiology laboratory, and incorporated into the database. The application of MolEpi tool to the Health System can provide prompt and accurate diagnosis, connected to relevant network information which can be intended for health professionals.
A maioria das pesquisas em epidemiologia molecular, diagnóstico molecular e genética evolutiva são confrontadas com o gerenciamento de grandes volumes de dados. Além disso, os dados utilizados em estudos de doenças patogênicas são complexos e geralmente derivam de instituições tais como hospitais ou laboratórios. Embora já existam propostas que conecte informações moleculares ao diagnóstico de patogenias, nenhuma delas utilizam ferramentas de bioinformática de alto desempenho incorporadas a um sistema e vinculada a um prontuário eletrônico do paciente. MolEpi foi desenvolvido como um sistema de gerenciamento de dados e informações dimensionado a saúde pública, incorporando informações clínicas e epidemiológicas sobre pacientes e dados moleculares de sequências do gene rRNA 16S de bactérias patogênicas. Para identificação destas bactérias foram utilizadas amostras biológicas (urina, secreções e purulentas de feridas, aspirado traqueal e sangue) e PCR seguida de sequenciamento e análise da região conservada codificadora de RNA ribossômico (rDNA) 16S. Este estratégia permite uma identificação bacteriana rápida, independente de conhecimento prévio da espécie de microrganismo em estudo. O MolEpi é um sistema facilmente atualizável com as sequências específicas de bancos como Genbank(NCBI), RDP-II (Ribosomal Database Project - MSU) e GreenGene (LBL). A partir da confirmação e validação das sequências dos isolados clínicos, estas podem ser utilizadas como referência na identificação de outros microrganismos desconhecidos. Neste sentido, foi estabelecido um banco de dados local, representativo do perfil de patógenos encontrados na unidade hospitalar de estudo e objeto de vigilância epidemiológica. Para o desenvolvimento do MolEpi, utilizamos a linguagem Java e banco de dados PostgreSQL8.3. Foi desenvolvido também o BACSearch, que possui os seguintes programas: para o processamento de sequências de rDNA 16S utilizamos os frameworks BioJava; para alinhamento múltiplo foi implementado o ClustalW2, MAFFT e o MUSCLE e para edição do alinhamento múltiplo e análise filogenética foi utilizado JalView R⃝2.4.0b2. O sistema foi validado com 200 espécimes clínicos identificadas e isoladas de sítios de infecção hospitalar. As sequências de DNA produzidas a partir destas amostras foram submetidas ao BLAST, utilizando a ferramenta desenvolvida, identificando Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiela pneumonie e Staphylococcus aureus como os principais patógenos correspondentes. Os dados sobre o padrão de resistência das espécies foram obtidos em laboratório de microbiologia e incorporados ao banco de dados. A aplicação do MolEpi ao Sistema Único de Saúde poderá fornecer diagnósticos mais rápidos, precisos, e interligados a uma rede de informações relevantes para o profissional de saúde.
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Silva, Daniel Garcia. "Mapeamento genético de marcadores DArT (Diversity Arrays Technology) em cana-de-açúcar (Saccharum spp.)." Universidade Federal de Goiás, 2012. http://repositorio.bc.ufg.br/tede/handle/tede/4689.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Sugarcane is an important crop, cultivated in more than 90 countries, occupying an area of approximately 20 million of hectares. Modern varieties (Saccharum spp.) are highly heterozygous interspecific hybrids, polyploids and often aneuploids, with chromosome numbers between 100 and 130. Such characteristics explain the common opinion that the genome of sugarcane is the most complex among cultivated species, posing a challenge to breeding programs. As a contribution to the understanding of this complex genomic architecture, this study aimed to build the first linkage maps using exclusively DArT markers in sugarcane. The maps were built using a progeny derived from the cross between varieties largely used in the Brazilian breeding program of RIDESA (RB97327 x RB72454). The initial mapping population comprised 186 individuals. Total genomic DNA was extracted from axial buds, following the protocol of Al-Janabi et al. (1999). Using the DArT P/L core facility to generate DArT data, a total of 7680 markers were analyzed, of which 850 were polymorphic. The analysis of segregation patterns in the progeny revealed that 47% of the individuals in the progeny were in fact derived from selfing of the female parent RB97327. These individuals were analyzed as a distinct generation. Linkage analyses were then performed on two populations (from selfing and crossing) separately. The software OneMap was used to construct the maps. The established linkage criteria for linkage analysis were LOD-score ≥ 3.5 and recombination fraction ≤ 0.4. In the first map, built using data from individuals originated from selfing, from 850 polymorphic markers, 392 markers (segregating in a 3:1 manner) were used to create 80 linkage groups related to the variety RB97327. For the population derived from the biparental crossing, four linkage maps were built: an integrated map composed of 98 linkage groups including 632 markers (1:1 and 3:1); an integrated framework map, using a more conservative ordering criteria for the linkage groups, which was composed of 94 linkage groups; and two other linkage maps, one for each parent (RB97327 and RB72454), built to estimate the genome size of the varieties involved in this study. The total length of the linkage map built using data from individuals derived from selfing of the variety RB97327 was 828 cM. The total length of the integrated linkage map was 2848 cM. The lengths of the maps built for each parent, using data from individuals derived from crossing, were 1465 cM (RB97327) and 1976 cM (RB72454). Using the methodology of Hulbert et al. (1988), the estimated genome sizes for these varieties were 2811 cM e 3471 cM, respectively. The maps obtained in these cases covered a low percentage of the estimated genome sizes (52% and 57%). In spite of the low polymorphism, DArT markers showed to be an efficient technique to perform genotyping of sugarcane. Hundreds of polymorphic markers were generated in only one assay, using two methods of genome complexity reduction. These markers represent a new tool for genetic studies in sugarcane, especially if the low cost (USD/marker) involved in data production is considered.
A cana-de-açúcar é uma importante cultura, cultivada em mais de 90 países, ocupando uma área total de aproximadamente 20 milhões de hectares. As variedades modernas (Saccharum spp.) são híbridos interespecíficos altamente heterozigóticos, poliploides e frequentemente aneuploides, com número cromossômico variando de 100 a 130. Tais características proporcionaram ao genoma da cana-de-açúcar o título de mais complexo entre as espécies cultivadas, o que representa um desafio para os programas de melhoramento genético da cultura. No intuito de contribuir com dados que auxiliem na compreensão dessa complexa arquitetura genômica, o presente estudo objetivou a construção dos primeiros mapas de ligação para cana-de-açúcar utilizando exclusivamente marcadores DArT, avaliados na progênie derivada do cruzamento de variedades amplamente utilizadas nos programas de melhoramento da RIDESA (RB97327 x RB72454). A população inicial de mapeamento foi composta por 186 indivíduos. O DNA genômico foi extraído de gemas axiais, seguindo o protocolo proposto por Al-Janabi et al. (1999). Após a extração, quantificação e homogeneização da concentração de DNA das amostras, o material foi enviado para a empresa DArT P/L para a geração dos marcadores DArT. Um total de 7680 locos foi analisado, dos quais 850 se apresentaram polimórficos. A análise dos padrões de segregação obtidos na progênie revelou que 47% dos indivíduos da progênie avaliada foram provenientes de autofecundação do genitor feminino RB97327. Os indivíduos identificados como provenientes de autofecundação foram analisados como uma geração distinta. As análises de ligação foram realizadas nas duas populações separadamente. O software OneMap foi utilizado para a construção dos mapas. Os critérios estabelecidos para proceder com as análises de ligação foram LOD-score ≥ 3,5 e fração de recombinação ≤ 0,4. No primeiro mapa, originário da população de autofecundação, dos 850 marcadores polimórficos, 392 marcadores com segregação 3:1 foram utilizados para originar 80 grupos de ligação referentes à variedade RB97327. Para a população derivada do cruzamento biparental foram construídos quatro mapas de ligação: um mapa integrado composto por 98 grupos de ligação a partir da análise de 632 marcadores (com segregações 1:1 e 3:1); um mapa framework integrado, construído a partir de uma ordenação mais refinada dos marcadores dentro de cada um dos grupos de ligação, o qual foi composto por 94 grupos de ligação; e, com o objetivo de se estimar o tamanho do genoma das variedades envolvidas neste estudo, dois mapas de ligação, um para cada genitor (RB97327 e RB72454). O comprimento total do primeiro mapa, referente à variedade RB97327, foi de 828cM. O comprimento total do mapa integrado foi de 2848 cM. Os comprimentos totais dos mapas obtidos para cada um dos genitores, gerados a partir de dados da população de cruzamento biparental, foram de 1465Cm (RB97327) e de 1976 cM (RB72454). Utilizando a metodologia de Hulbert et al. (1988), os tamanhos estimados dos genomas das variedades RB97327 e RB72454 foram 2811 cM e 3471 cM, respectivamente. Assim, pode-se afirmar que os mapas obtidos neste caso apresentaram baixa cobertura (52% e 57%), perante o tamanho estimado dos genomas. Apesar do baixo polimorfismo, os marcadores DArT se mostraram eficientes na genotipagem de progênies de cana-de-açúcar, pois, centenas de marcas polimórficas foram geradas em apenas um ensaio, com dois métodos de redução de complexidade. Estes marcadores representam uma nova ferramenta para o desenvolvimento de estudos genéticos em cana-de-açúcar, principalmente se considerado o baixo custo (R$/marcador) envolvido na obtenção dos genótipos.
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Ernenwein, René. "Mise au point d'un systeme de programmes vectorise et multitaches pour le calcul ab initio scf/ci sur cray 2." Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13128.
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Application du formalisme de mc murchie et davidson au calcul vectoriel des integrales mono et bielectroniques en tirant parti de l'architecture a la fois vectorielle et parallele au superordinateur cray 2. Gain substantiel de performance dans le calcul scf par une utilisation judicieuse des elements de supermatrice reordonnes par rapport aux deux premiers indices. Par utilisation conjointe de la grande memoire et de l'adressage indirect vectoriel du cray 2, vectorisation du calcul de ces elements et des contributions a la matrice de fock
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Keselowsky, Benjamin George. "Engineering surgaces to direct integrin binding and signaling to promote osteoblast differentiation." Available online, Georgia Institute of Technology, 2004, 2004. http://etd.gatech.edu/theses/available/etd-03152004-111413/.
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Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2004.David Collard, Committee Member ; Robert Guldberg, Committee Member ; Cheng Zhu, Committee Member ; Elliot Chaikoff, Committee Member ; Harish Radhakrishna, Committee Member ; Andres J. Garcia, Committee Chair. Includes bibliographical references.
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Terreni, Mariaelena. "GCN5-Dependent Acetylation of HIV-1 Integrase Enhances Viral Integration." Doctoral thesis, Scuola Normale Superiore, 2013. http://hdl.handle.net/11384/85968.
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Carvalho, Luciana Luzia de. "Modelagem molecular de uma série de compostos inibidores da enzima integrase do vírus HIV-1." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/75/75131/tde-16092011-160536/.
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Uma etapa essencial no ciclo de vida do vírus HIV é a integração do DNA viral no cromossomo hospedeiro. Essa etapa é catalisada pela enzima integrase (IN) de 32-kDa. HIV-1 IN é um importante e validado alvo, e as drogas que inibem seletivamente a enzima, quando utilizadas em combinação com os inibidores da transcriptase reversa (RT) e protease (PR), são consideradas altamente eficazes em suprimir a replicação viral. IN catalisa dois processos enzimáticos designados por 3\' processamento e transferência de DNA. Agentes ativos contra integrase, inibindo a etapa de transferência da vertente já estão em fase clínica. O fármaco Raltegravir® é o primeiro nesta nova classe. Os ensaios clínicos no tratamento em novos pacientes têm uma atividade anti-retroviral potente e bem tolerado. Dada a sua potência, segurança e novo mecanismo de ação, os inibidores da integrase representam um importante avanço terapêutico contra o HIV-1. Na presente tese de doutorado, foram realizados estudos quimiométricos utilizando descritores teóricos e QSAR bi- (2D) e tridimensionais (3D) empregando, respectivamente, as técnicas holograma QSAR (HQSAR) e a análise comparativa dos campos moleculares (CoMFA), visando à geração de modelos preditivos para um conjunto de inibidores da integrase do vírus HIV-1. Modelos de QSAR com boa consistência interna, habilidade preditiva e estabilidade foram obtidos em todos os casos. Os modelos gerados, associados às informações obtidas pelos mapas de contribuição 2D e de contorno 3D, são guias químico-medicinais úteis no planejamento de novos inibidores mais potentes e seletivos da integrase do HIV-1.An essential step in the HIV life cycle is integration of the viral DNA into the host chromosome. This step is catalyzed by a 32-kDa viral enzyme HIV integrase (IN). HIV-1 IN is an important and validated target, and the drugs that selectively inhibit this enzyme, when used in combination with reverse transcriptase (RT) and protease (PR) inhibitors, are believed to be highly effective in suppressing the viral replication. IN catalyzes two discrete enzymatic processes referred as 3\' processing and DNA strand transfer. Agents active against HIV-1, which target the viral integrase by inhibiting the strand transfer step of integration, have now initialized the clinical trials. The Raltegravir® is the first drug in this new class. Clinical trials in treatment-experienced and in treatment-naive patients have shown that raltegravir-containing regimens have potent antiretroviral activity and are well tolerated. Given their potency, safety and novel mechanism of action, integrase inhibitors represent an important advance in HIV-1 therapy. In the present thesis, Bi- and Tridimensional Quantitative Structure-Activity Relationship (QSAR) studies were performed applying chemometric methods based on theoretical descriptors, Comparative Molecular Field Analysis (CoMFA) and Holograma QSAR (HQSAR) techniques, aiming to generate predictive models for a large set of HIV-1 IN inhibitors. QSAR models presenting good internal consistency, predictive power and stability were obtained in all cases. The final models along with the information resulted by 2D contribution and 3D contour maps should be useful in the design of new inhibitors with increased potency and selective within the chemical diversity of the data.
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Tatavarthy, Aparna. "Molecular Subtyping and Antibiotic Resistance Analysis of Salmonella Species." [Tampa, Fla] : University of South Florida, 2005. http://purl.fcla.edu/usf/dc/et/SFE0001307.
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Patel, Pratiq A. "Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1382064973.
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Cipcigan, Flaviu Serban. "Electronically coarse grained molecular model of water." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28814.
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Electronic coarse graining is a technique improving the predictive power of molecular dynamics simulations by representing electrons via a quantum harmonic oscillator. This construction, known as a Quantum Drude Oscillator, provides all molecular long-range responses by uniting many-body dispersion, polarisation and cross interactions to all orders. To demonstrate the predictive power of electronic coarse graining and provide insights into the physics of water, a molecular model of water based on Quantum Drude Oscillators is developed. The model is parametrised to the properties of an isolated molecule and a single cut through the dimer energy surface. Such a parametrisation makes the condensed phase properties of the model a prediction rather than a fitting target. These properties are studied in four environments via two-temperature adiabatic path integral molecular dynamics: a proton ordered ice, the liquid{vapour interface, supercritical and supercooled water. In all these environments, the model predicts a condensed phase in excellent agreement with experiment, showing impressive transferability. It predicts correct densities and pressures in liquid water from 220 K to 647 K, and a correct temperature of maximum density. Furthermore, it predicts the surface tension, the liquid-vapour critical point, density of ice II, and radial distribution functions across all conditions studied. The model also provides insight into the relationship between the molecular structure of water and its condensed phase properties. An asymmetry between donor and acceptor hydrogen bonds is identified as the molecular scale mechanism responsible for the surface orientation of water molecules. The dipole moment is identified as a molecular scale signature of liquid-like and gas-like regions in supercritical water. Finally, a link between the coordination number and the anomalous thermal expansion of the second coordination shell is also presented.
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Geberhiwot, Tarekegn. "Laminin of platelets and leukocytes : molecular characterization, integrin receptors and functional roles /." Stockholm, 2000. http://diss.kib.ki.se/2000/20001212gebe/.
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Comber, Kate. "Investigation into the molecular mechanisms governing Drosophila embryonic hemocyte migration in vivo." Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606669.
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Accumulating evidence highlights the importance of studying the migration of cells within the context of their natural environment as manipulating the substrate on which a cell is migrating can have a dramatic impact on the mode/mechanisms employed by cells during migration. Central to this phenomenon is the requirement of adhesion to the ECM in order to gain traction during migration. Integrins constitute the main family of cell receptors involved in mediating cell-ECM interactions during motility. Whilst traditionally two-dimensional cell culture studies have placed emphasis on the importance of these receptors for spreading and migration, it has become evident that within more confined environments these receptors, at least for some cell types, are less crucial. In this research we utilise Drosophila embryonic hemocytes as an in vivo model for cell migration. We show that whilst hemocytes migrate within confined environments in vivo, these cells depend on integrins for powering both developmental and inflammatory migrations. Given the close association between these receptors and the actin cytoskeleton we were surprised to discover that removal of the main β integrin subunit, Myospheroid, did not affect cell spreading in vivo and had only a small impact on lamellipodial structure and dynamics. Furthermore we discovered that, in contrast to other cell types previously analysed, removal of this integrin subunit in hemocytes was not accompanied by an increase in the rate of actin retrograde flow within the protrusions, which we believe could reflect abrogation of a positive feedback between Rho, ROCK and Myosin II contraction. Instead, we discover a key role for integrins in regulating the microtubule cytoskeleton, in the maintenance of a polarised microtubule bundle, termed a ‘microtubule-arm’. Although the molecular mechanisms by which this stabilisation is coordinated have yet to be identified, this provides important insight into the co-regulation of adhesion and microtubule cytoskeleton important for the migratory behaviour of these cells. Cell migration reflects the complex and integrated regulation of the actin cytoskeleton by diverse families of actin regulatory proteins. Using hemocytes as a model system, we also explore the regulatory interactions between two main actin regulatory proteins, Diaphanous and Enabled, in vivo. Whilst the function of these proteins in the formation of filopodial protrusions is overlapping, recent research has highlighted the ability of these proteins to regulate the activity of one another. We find that co-expression of Enabled in hemocytes is able to rescue the morphological and migratory defects resulting from overexpression of active Diaphanous. Thus, data here presents Enabled as a negative regulator of Diaphanous, which may play an important role in the migration of hemocytes in vivo.
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Allouch, Awatef. "Cellular factors that interact with acetylated integrase: new insights in HIV - 1 integration." Doctoral thesis, Scuola Normale Superiore, 2011. http://hdl.handle.net/11384/85958.
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Santos, Giovanni César dos [UNESP]. "Estudo das estruturas terciária e quaternária de proteínas por espalhamento de raios X a baixos ângulos integrado a técnicas de modelagem." Universidade Estadual Paulista (UNESP), 2003. http://hdl.handle.net/11449/100478.
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O espalhamento de raios X a baixos ângulos foi utilizado para obter informações sobre a estrutura terciária e quaternária de várias proteínas das quais, também, foram verificadas a ocorrência de mudanças conformacionais induzidas por variação de pH e adição de ligantes. A técnica de SAXS integrada a programas de modelagem, como MODELLER e GRAMM, demonstrou ter grande utilidade para a seleção de modelos de proteínas de estruturas desconhecidas e mesmo para a construção de complexos. A combinação dessas técnicas também ajudou a obter informações importantes que auxiliaram na compreensão do comportamento em solução de algumas proteínas, podendo contribuir no desenvolvimento de fármacos para o tratamento de determinadas doenças. Nessa linha, entre outros resultados importantes, podem ser destacados os de duas enzimas analisadas: a PNP humana, da qual ficou comprovado que a estrutura cristalina trimérica é conservada em solução; e a EPSP Sintase de M. tuberculosis, que passa de um estado mais aberto para outro mais fechado na presença de fosfato.
Small angle X-ray scattering has been used to get information on the tertiary and quaternary structure of different proteins including induced conformational changes due to pH variation and ligand addition. An integration between SAXS techniques and modeling programs like MODELLER and GRAMM, proved to be very useful for models selection of protein with unknown structures and also for building up protein complexes. Combining SAXS techniques and modeling programs allowed us to get information on the behavior of several proteins in solution what may be used as a new tool in drug development. With this purpose two enzymes have been studied: human PNP, for which we proved that the trimmeric crystalline structure is conserved in solution, and for M. tuberculosis EPSP Sintase, which changes from an open state to another more closed due to the presence of phosphate ions.
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Santos, Giovanni César dos. "Estudo das estruturas terciária e quaternária de proteínas por espalhamento de raios X a baixos ângulos integrado a técnicas de modelagem /." São José do Rio Preto : [s.n.], 2003. http://hdl.handle.net/11449/100478.
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Orientador: Johnny Rizzieri OlivieriBanca: Yvone Primerando Mascarenhas
Banca: Luis Fernando Delboni
Banca: Sandra Helena Pulcinelli
Banca: Walter Filgueira de Azevedo Júnior
Resumo: O espalhamento de raios X a baixos ângulos foi utilizado para obter informações sobre a estrutura terciária e quaternária de várias proteínas das quais, também, foram verificadas a ocorrência de mudanças conformacionais induzidas por variação de pH e adição de ligantes. A técnica de SAXS integrada a programas de modelagem, como MODELLER e GRAMM, demonstrou ter grande utilidade para a seleção de modelos de proteínas de estruturas desconhecidas e mesmo para a construção de complexos. A combinação dessas técnicas também ajudou a obter informações importantes que auxiliaram na compreensão do comportamento em solução de algumas proteínas, podendo contribuir no desenvolvimento de fármacos para o tratamento de determinadas doenças. Nessa linha, entre outros resultados importantes, podem ser destacados os de duas enzimas analisadas: a PNP humana, da qual ficou comprovado que a estrutura cristalina trimérica é conservada em solução; e a EPSP Sintase de M. tuberculosis, que passa de um estado mais aberto para outro mais fechado na presença de fosfato.
Abstract: Small angle X-ray scattering has been used to get information on the tertiary and quaternary structure of different proteins including induced conformational changes due to pH variation and ligand addition. An integration between SAXS techniques and modeling programs like MODELLER and GRAMM, proved to be very useful for models selection of protein with unknown structures and also for building up protein complexes. Combining SAXS techniques and modeling programs allowed us to get information on the behavior of several proteins in solution what may be used as a new tool in drug development. With this purpose two enzymes have been studied: human PNP, for which we proved that the trimmeric crystalline structure is conserved in solution, and for M. tuberculosis EPSP Sintase, which changes from an open state to another more closed due to the presence of phosphate ions.
Doutor
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Kido, Kentaro. "Theoretical Studies of Chemical Processes in Multi-Component Solution Systems Based on Integral Equation Theory for Molecular Liquids." 京都大学 (Kyoto University), 2012. http://hdl.handle.net/2433/158077.
Full text
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VALENTINI, PAOLA. "Role of Integrase Acetylation in HIV-1 Replication Cycle and Search for Acetylation Inhibitors." Doctoral thesis, Scuola Normale Superiore, 2013. http://hdl.handle.net/11384/85971.
Full textAbstract:
HIV-1 integrase catalyzes the integration of the viral DNA into the genome
of the host cells. This irreversible event is crucial to the pathogenesis of the
infection and complicates its eradication both by the immune systems and by
pharmacological treatments.
The mode of action of this viral enzyme is still not completely
characterized, although full understanding of some key aspects, as the
mechanism of integration site selection, are relevant both for the development
of new anti-integrase drugs and for potential application of HIV-derived vectors
for gene therapy.
Our group has demonstrated that integrase is post-translationally acetylated
by two cellular histone-acetyl transferases (HATs), chromatin-modifying
enzymes whose major role is that of transcriptional co-activators. Integrase
acetylation is important for the viral infectivity and interaction with HATs
might be one of the determinants of HIV-1 preferential integration in actively
transcribed genomic regions.
Integrase is a poorly exploited target of anti-HIV drugs, while traditional
therapies based on combinations of reverse transcriptase inhibitors and protease
inhibitors are facing the rapid diffusion of multi-drugs resistant viral variants.
This pushes research towards new drugs and new targets, including integrase
and, even better, its interactions with cellular cofactors like, for instance, HATs.
This thesis deals with the selection of novel inhibitors of integrase
acetylation, to be used as lead compound for the development of new
generation anti-integrase drugs.
A selective inhibitor of integrase acetylation was identifyied through in
vitro screening of a library of synthetic compounds, designed based on the
structures of natural HAT inhibitors. Structure-Activity-Relationships (SAR)
studies led to the rational design of a smaller set of compounds, whose activity
was tested with in vitro and in vivo assays. Finally, one molecule was chosen
for further studies with HIV-1 derived lentiviral vectors. This cinnamoil
compound was able to inhibit integrase acetylation in the virus and reduced
viral integration in infected cells. In a reciprocal experiment, viral vectors
containing hyper-acetylated integrase were generated by trans-incorporation of
fusion integrase-HAT proteins, or of isolated HAT domains. The enhanced
infectivity of these virions confirmed the role of acetylation for integrase
function.
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Pessoa, Oseias Alves. "Cálculo das seções de choque diferenciais e integrais para excitação de elétrons de camadas internas da molécula de C2H2." Florianópolis, SC, 2003. http://repositorio.ufsc.br/xmlui/handle/123456789/84840.
Full textAbstract:
Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Físicas e Matemáticas. Programa de Pós-Graduação em Física.Made available in DSpace on 2012-10-20T12:59:17Z (GMT). No. of bitstreams: 1 196653.pdf: 505951 bytes, checksum: 64254e8eb6ac68c2cd7e1294582360e5 (MD5)
Cálculo das seções de choque para o espalhamento de elétrons por moléculas de acetileno, para as transições e , na faixa de energias de 300-800 eV . Aplicamos o método da onda distorcida (MOD) combinado com o método variacional iterativo de Schwinger (SVIM).
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Lygatsika, Ioanna-Maria. "Méthodes numériques pour les discrétisations gaussiennes des problèmes en structure électronique." Electronic Thesis or Diss., Sorbonne université, 2024. http://www.theses.fr/2024SORUS149.
Full textAbstract:
La simulation moléculaire est l'un des outils les plus courants de la chimie moderne. Les calculs réalisés au cours de ces simulations présentent souvent des difficultés, qui conduisent à une réduction de leurs performances lorsque les systèmes simulés sont des larges molécules composées de plusieurs atomes. Cette thèse se focalise sur les limitations liées à l'utilisation de fonctions de base centrées sur les atomes des molécules pour la discrétisation des équations de type Schrödinger, qui est un type de discrétisation très populaire en chimie quantique. Nous adoptons une approche d'analyse numérique pour formuler et traiter ces limitations. Le présent travail aborde deux questions fondamentales liées aux éléments de base de type gaussien centrés sur les atomes, à savoir l'évaluation des intégrales moléculaires sur les fonctions de base et la génération des éléments de cette base. Ces deux points ont un impact sur le coût de calcul et les exigences en mémoire des simulations moléculaires. Notre objectif principal est de concevoir des nouvelles méthodes mathématiques ainsi que des nouveaux algorithmes efficaces qui améliorent les simulations moléculaires modernes. Les principales contributions de cette thèse sont les deux suivantes : premièrement, l'accélération de l'évaluation des intégrales moléculaires sur les fonctions de base centrées sur les atomes et, deuxièmement, la proposition d'estimateurs d'erreur a posteriori pour les discrétisations centrées sur les atomes des problèmes linéaires à valeurs propres. Pour le premier objectif, nous avons développé une nouvelle méthode d'ajustement de densité ("Density Fitting" en anglais) pour l’approximation de la densité électronique, complétant les méthodes existantes dans la littérature, qui vise à réduire le coût de calcul en utilisant des approximations de rang faible et creuses, basées sur l’élimination des dépendances linéaires et la décomposition de Cholesky avec pivot. Notre schéma est présenté en utilisant un nouveau formalisme d'optimisation discrète et de recherche du plus court chemin sur les graphes. En outre, nous avons généralisé nos techniques en développant un nouveau schéma d'ajustement de densité indépendant des positions atomiques, en utilisant la méthode des bases réduites. La performance numérique de nos méthodes est démontrée par les résultats numériques des calculs d'énergie d'interaction intermoléculaire basée sur les densités en chimie. Pour le second objectif, notre travail constitue une extension de la théorie de l'estimation de l'erreur a posteriori basée sur les résidus des discrétisations gaussiennes sur des domaines non bornés. Un tel cadre, qui est couramment utilisé en chimie, n'a pas fait l'objet d'études théoriques dans la littérature mathématique jusqu'à présent. Notre contribution dans ce domaine permet la génération adaptative et automatique des bases centrées sur les atomes. Nous présentons des résultats numériques préliminaires des calculs en structure électronique afin d'illustrer un exemple d’application de nos estimateurs d'erreur a posteriori. En résumé, les bases de discrétisation centrées sur les atomes sont largement utilisées dans les simulations moléculaires. Les conclusions de cette thèse contribuent à la compréhension de telles bases du point de vue numérique, tout en proposant des solutions qui permettent l'amélioration des simulations moléculaires en chimieMolecular simulation is among the most common tools in modern chemistry. Suchsimulations often suffer from several computational bottlenecks that reducetheir performance when applied to large systems of molecules or atoms. Thisthesis primarily focuses on the limitations arising from the use ofatom-centered basis functions for the discretization of Schrödinger-typeequations for molecules, which is a popular type of discretization in quantumchemistry applications. We adopt a numerical analysis approach to formulate andtackle such limitations. The present work addresses two of the most impactfulissues related to Gaussian-type atom-centered basis sets, namely, the evaluationof integrals on the basis functions and the generation of such basis sets. Bothissues significantly affect the computational cost and memory requirements ofmolecular simulations. Our main goal is to design novel mathematical methods aswell as new efficient low-complexity algorithms improving modern molecularsimulations. The main contributions of this thesis are twofold: first,accelerating the evaluation of high-dimensional integrals on atom-centered basisfunctions, and, second, establishing a posteriori error estimators foratom-centered discretizations of linear eigenvalue problems. For the firstpurpose, we developed a new density fitting method for approximating theone-electron density, beyond the existing classical and robust density fittingmethods of the literature, achieving tunable cost reduction via sparse low-rankapproximation based on linear dependency elimination and the pivoted Choleskydecomposition. Our scheme is presented using a novel formalism of discreteoptimization and shortest path search on graphs. In addition, we generalizedour main techniques by developing a new atomic-position-independent densityfitting scheme using the reduced basis method. The numerical performance of ourmethods is demonstrated by numerical results of an application to density-basedintermolecular electrostatic interaction energy calculations in chemistry. Forthe second purpose, our work constitutes an extension of residual-based aposteriori error estimation theory to Gaussian discretizations over unboundeddomains. Such a setting, which is routinely used in chemistry, was lackingtheoretical investigation in the mathematical literature up to now. Ourcontribution on this domain paves the way towards adaptive and automaticgeneration of atom-centered basis sets. As numerical evidence, we presentpreliminary numerical results of an application to electronic structure theorycalculations. To sum up, atom-centered Gaussian basis sets are widely used inmolecular simulations. The conclusions of this thesis provide insights to thenumerical analysis as well as to the computational aspects of the use of suchbasis sets in practice, while numerically demonstrating the ability of ourmethodologies to improve realistic simulations in chemistry