Poorly water-soluble drugs (PWSDs), to date, require advanced formulation techniques to improve solubility and achieve the required plasma concentration to show a therapeutic effect when orally administered. Lipid-based formulations (LBFs) are an enabling strategy that is being used to improve the oral delivery of PWSDs. The aim of this study was to investigate the effect of lipid-based formulation, Type IIIA-LC, on the solubilization patterns of PWSDs, namely, carvedilol and felodipine. Solubility studies, for both drugs, were performed with LBF dispersed in -1) dog intestinal fluid (DIF), and 2) water, to identify and compare the extent of solubility in different matrices, and in silico to identify interesting patterns with any correlations in experimental and computational data. Solubility studies showed that carvedilol had better solubility in LBF when compared to felodipine. Computational studies showed that both drugs solubilized in the colloid in both digested and undigested states. Effect of drug loading had no significant difference on the solubilization patterns of both drugs. The maximum drug loading done was for 100 molecules though there is the possibility of the colloid having a higher capacity. Digestion did not seem to have a significant effect on the distribution of both drugs. In vitro and in silico data were in qualitative agreement and therefore, this computational model can be further used to study the specific processes causing solubilization, improvement, and development of new LBFs.

Proteine spielen auf der zellulären Ebene eines Organismus eine fundamentale Rolle. Sie sind quasi die „Maschinen“ der Zelle. Ihre Bedeutung wird nicht zuletzt in ihrem Namen deutlich, welcher 1838 erstmals von J. Berzelius verwendet wurde und „das Erste“, „das Wichtigste“ bedeutet. Proteine sind aus Aminosäuren aufgebaute Moleküle. Unter physiologischen Bedingungen besitzen sie eine definierte dreidimensionale Gestalt, welche für ihre biologische Funktion bestimmend ist. Es wird heutzutage davon ausgegangen, dass diese dreidimensionale, stabile Struktur von Proteinen eindeutig durch die Abfolge der einzelnen Aminosäuren, der Sequenz, bestimmt ist. Diese Abfolge ist für jedes Protein in der Desoxyribonukleinsäure (DNS) gespeichert. Es ist allerdings eines der größten ungelösten Probleme der letzten Jahrzehnte, wie die Beziehung zwischen Sequenz und 3D-Struktur tatsächlich aussieht. Die Beantwortung dieser Fragestellung erfordert interdisziplinäre Ansätze aus Biologie, Informatik und Physik. In dieser Arbeit werden mit Hilfe von Methoden der theoretischen (Bio-) Physik einige der damit verbundenen Aspekte untersucht. Das Hauptaugenmerk liegt dabei auf Wechselwirkungen der einzelnen Aminosäuren eines Proteins untereinander, wofür in dieser Arbeit ein entsprechendes Energiemodell entwickelt wurde. Es werden Grundzustände sowie Energielandschaften untersucht und mit experimentellen Daten verglichen. Die Stärke der Wechselwirkung einzelner Aminosäuren erlaubt zusätzlich Aussagen über die Stabilität von Proteinen bezüglich mechanischer Kräfte. Die vorliegende Arbeit unterteilt sich wie folgt: Kapitel 2 dient der Einleitung und stellt Proteine und ihre Funktionen dar. Kapitel 3 stellt die Modellierung der Proteinstrukturen in zwei verschiedenen Modellen vor, welche in dieser Arbeit entwickelt wurden, um 3D-Strukturen von Proteinen zu beschreiben. Anschließend wird in Kapitel 4 ein Algorithmus zum Auffinden des exakten Energieminimums dargestellt. Kapitel 5 beschäftigt sich mit der Frage, wie eine geeignete diskrete Energiefunktion aus experimentellen Daten gewonnen werden kann. In Kapitel 6 werden erste Ergebnisse dieses Modells dargestellt. Der Frage, ob der experimentell bestimmte Zustand dem energetischen Grundzustand eines Proteins entspricht, wird in Kapitel 7 nachgegangen. Die beiden Kapitel 8 und 9 zeigen die Anwendung des Modells an zwei Proteinen, dem Tryptophan cage protein als dem kleinsten, stabilen Protein und Kinesin, einem Motorprotein, für welches 2007 aufschlussreiche Experimente zur mechanischen Stabilität durchgeführt wurden. Kapitel 10 bis 12 widmen sich Membranproteinen. Dabei beschäftigt sich Kapitel 10 mit der Vorhersage von stabilen Bereichen (sog. Entfaltungsbarrieren) unter externer Krafteinwirkung. Zu Beginn wird eine kurze Einleitung zu Membranproteinen gegeben. Im folgenden Kapitel 11 wird die Entfaltung mit Hilfe des Modells und Monte-Carlo-Techniken simuliert. Mit dem an Membranproteine angepassten Wechselwirkungsmodell ist es möglich, den Einfluss von Mutationen auch ohne explizite strukturelle Informationen vorherzusagen. Dieses Thema wird in Kapitel 12 diskutiert. Die Beziehung zwischen Primär- und Tertiärstruktur eines Proteins wird in Kapitel 13 behandelt. Es wird ein Ansatz skizziert, welcher in der Lage ist, Strukturbeziehungen zwischen Proteinen zu detektieren, die mit herkömmlichen Methoden der Bioinformatik nicht gefunden werden können. Die letzten beiden Kapitel schließlich geben eine Zusammenfassung bzw. einen Ausblick auf künftige Entwicklungen und Anwendungen des Modells.

The theory of the lamellar eutectoid reaction by volume diffusion has been extended to account for solute segregation within the product phases and the effect of dilute third element additions. It has been demonstrated for symmetric binary systems that the segregation can account for 10% or more of the free energy stored in the product phases and can lead correspondingly to a predicted lamellar spacings appreciably greater than those obtained when segregation is neglected. This segregation is relatively high in the systems Cu-In, Cu-Be and Ag-Cd and may account for the fact that a secondary coarse-grained pearlitic reaction follows the initial fine grained one in these systems. The binary theory has been-used to analyse the available data for the eutectoid reaction in the Cu-Al and Fe-C systems and satisfactory agreement is obtained. The theory for ternary systems, while complete in principle, proves to be. intractable in all but the simplest version of the solution thermodynamics. It is concluded that the effect of the third element on the binary eutectoid reaction is mainly through its effect on the phase diagram, the ternary cross effects in the diffusion matrix tending to cancel out. Any additional element which lowers the eutectoid temperature will retard the reaction. / Thesis / Doctor of Philosophy (PhD)

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Geosynthetic reinforced soil (GRS) is a soil improvement technology in which closely spaced horizontal layers of geosynthetic are embedded in a soil mass to provide lateral support and increase strength. GRS is popular due to a relatively new application for bridge support, as well as long-standing application in mechanically stabilized earth walls. Several different GRS design methods have been used, and some are application-specific and not based on fundamental principles of mechanics. Because consensus regarding fundamental behavior of GRS is lacking, numerical and mathematical analyses were performed for laboratory tests obtained from the published literature of GRS under triaxial compression in consolidated-drained conditions. A three-dimensional numerical model was developed using FLAC3D. An existing constitutive model for the soil component was modified to incorporate confining pressure dependency of friction angle and dilation parameters, while retaining the constitutive model's ability to represent nonlinear stress-strain response and plastic yield. Procedures to obtain the parameter values from drained triaxial compression tests on soil specimens were developed. A method to estimate the parameter values from particle size distribution and relative compaction was also developed. The geosynthetic reinforcement was represented by two-dimensional orthotropic elements with soil-geosynthetic interfaces on each side. Comparisons between the numerical analyses and laboratory tests exhibited good agreement for strains from zero to 3% for tests with 1 to 3 layers of reinforcement. As failure is approached at larger strains, agreement was good for specimens that had 1 or 2 layers of reinforcement and soil friction angle less than 40 degrees. For other conditions, the numerical model experienced convergence problems that could not be overcome by mesh refinement or reducing the applied loading rate; however, it appears that, if convergence problems can be solved, the numerical model may provide a mechanics-based representation of GRS behavior, at least for triaxial test conditions. Three mathematical theories of GRS failure available in published literature were applied to the laboratory triaxial tests. Comparisons between the theories and the tests results demonstrated that all three theories have important limitations. These numerical and mathematical evaluations of laboratory GRS tests provided a basis for recommending further research. / Ph. D.

Theoretical studies of the molecular mechanisms responsible for the formation and stability of protein complexes have gained importance due to their practical applications in the understanding of the molecular basis of several diseases, in protein engineering and biotechnology. The objective of this project is to critically analyze and refine a coarse-grained force field for protein-protein interactions based on experimental thermodynamic properties and to apply it to cancer-related S100A4 protein system. Our ultimate goal is to generate knowledge for a better understanding of the physical mechanisms responsible for the association of particular proteins in different environments. We studied the role of short and long-range interactions on the complexation of homo-associations. Furthermore, we analyzed the influence of the pH and its correlation with the charge regulation mechanism. We analyzed and refined the adjustable Lennard-Jones parameter for a mesoscopic model based on experimental second virial data for lysozyme, chymotrypsinogen, and ribonuclease A via Monte Carlo simulations. From of that, the S100A3 protein was used to test the new calibrated parameters. Finally, we evaluated the dimerization process of S100A4 proteins, observing the role of physical-chemistry variables involved in the thermodynamical stability of different oligomers. / Estudos teóricos dos mecanismos moleculares responsáveis pela formação e estabilidade dos complexos de proteínas vêm ganhando importância devido às suas aplicações práticas no entendimento da base molecular de várias doenças, em engenharia de proteínas e biotecnologia. O objetivo deste projeto é analisar criticamente e aperfeiçoar um campo de força de granulidade grossa para interação proteína-proteína com base em propriedades termodinâmicas experimentais e aplicá-lo ao sistema proteico S100A4 relacionado com o câncer. Nosso objetivo final é gerar conhecimento para uma melhor compreensão dos mecanismos físicos responsáveis pelas associações de proteínas particulares em diferentes ambientes. Estudamos o papel das interações de curto e longo alcance na complexação de homo-associações. Além disso, analisamos a influência do pH e sua correlação com o mecanismo de regulação de cargas. Por meio de simulações Monte Carlo, analisamos e refinamos o parametro ajustável de Lennard-Jones para um modelo mesoscópico, usando dados experimentais do segundo virial para a lisozima, o quimotripsinogênio e a ribonuclease A. A partir disso, a proteína S100A3 foi usada para testar os novos parâmetros calibrados. Finalmente, foi avaliado o processo de dimerização das proteínas S100A4, observando o papel de algumas variáveis físico-químicas envolvidas na estabilidade termondinâmica de diferentes oligómeros.

No description available.

Theoretical studies of the molecular mechanisms responsible for the formation and stability of protein complexes have gained importance due to their practical applications in the understanding of the molecular basis of several diseases, in protein engineering and biotechnology. The objective of this project is to critically analyze and refine a coarse-grained force field for protein-protein interactions based on experimental thermodynamic properties and to apply it to cancer-related S100A4 protein system. Our ultimate goal is to generate knowledge for a better understanding of the physical mechanisms responsible for the association of particular proteins in different environments. We studied the role of short and long-range interactions on the complexation of homo-associations. Furthermore, we analyzed the influence of the pH and its correlation with the charge regulation mechanism. We analyzed and refined the adjustable Lennard-Jones parameter for a mesoscopic model based on experimental second virial data for lysozyme, chymotrypsinogen, and ribonuclease A via Monte Carlo simulations. From of that, the S100A3 protein was used to test the new calibrated parameters. Finally, we evaluated the dimerization process of S100A4 proteins, observing the role of physical-chemistry variables involved in the thermodynamical stability of different oligomers. / Estudos teóricos dos mecanismos moleculares responsáveis pela formação e estabilidade dos complexos de proteínas vêm ganhando importância devido às suas aplicações práticas no entendimento da base molecular de várias doenças, em engenharia de proteínas e biotecnologia. O objetivo deste projeto é analisar criticamente e aperfeiçoar um campo de força de granulidade grossa para interação proteína-proteína com base em propriedades termodinâmicas experimentais e aplicá-lo ao sistema proteico S100A4 relacionado com o câncer. Nosso objetivo final é gerar conhecimento para uma melhor compreensão dos mecanismos físicos responsáveis pelas associações de proteínas particulares em diferentes ambientes. Estudamos o papel das interações de curto e longo alcance na complexação de homo-associações. Além disso, analisamos a influência do pH e sua correlação com o mecanismo de regulação de cargas. Por meio de simulações Monte Carlo, analisamos e refinamos o parametro ajustável de Lennard-Jones para um modelo mesoscópico, usando dados experimentais do segundo virial para a lisozima, o quimotripsinogênio e a ribonuclease A. A partir disso, a proteína S100A3 foi usada para testar os novos parâmetros calibrados. Finalmente, foi avaliado o processo de dimerização das proteínas S100A4, observando o papel de algumas variáveis físico-químicas envolvidas na estabilidade termondinâmica de diferentes oligómeros.