Apresentamos uma série de estudos, baseados em simulações de Dinâmica Molecular no vácuo e em solução, sobre o processo de complexação das supramoléculas tetraethylester p-tert-butyl calix[4]arene (CLE) e tetramethylketone p-tert-butyl calix[4]arene (CLC) com os íons Pb2+ e Cd2+ e espécies neutras. Os modelos para as moléculas de calixareno e do solvente foram baseados no campo de forças OPLS-AA. Os parâmetros para os íons foram desenvolvidos a partir de uma metodologia de ajuste de valores de modo a reproduzirem simultaneamente propriedades termodinâmicas e estruturais obtidas experimentalmente ou por cálculos de QM/MM. As simulações no estado líquido nos mostraram que o CLE aprisiona os íons de maneira mais eficiente que o CLC, formando complexos mais estáveis. A complexação do íon desencadeia um efeito alostérico em ambos os calixarenos estudados, permitindo a complexação de uma molécula de acetonitrila na cavidade hidrofóbica estabilizando o complexo. Nas simulações com o CLC observamos que a complexação da acetonitrila é necessária para manter o íon ligado à cavidade hidrofílica, evidenciando a dependência desses complexos com esse solvente em específico. Apesar de observarmos que o CLE apresenta maior afinidade com os íons Pb2+ e Cd2+ que o CLC, somente futuras simulações utilizando a água como solvente poderão confirmar a viabilidade do uso desta molécula em sistemas destinados à despoluição ambiental. / We report a series of Molecular Dynamics simulations, in vacuum and in acetonitrile solution, on the complexation process of the calixarens tetraethylester p-tert-butyl calix[4]arene (CLE) and tetramethylketone p-tert-butyl calix[4]arene (CLC) with Pb2+ and Cd2+ anions and neutral species. The solvent and calixarene molecules were modeled based on the OPLS-AA force field. The parameters for the ions were adjusted to simultaneously reproduce some structural and thermodynamic properties obtained either experimentally or from QM/MM calculations. The simulations in the liquid phase show CLE to be more efficient than CLC in trapping the studied metal ions, leading to more stable complexes. Ion complexation gives rise to an allosteric effect by which a solvent molecule is trapped in the hydrophobic cavity giving rise to further stabilization of the complex. Simulations on CLC show that formation of the calixarene-acetonitrile adduct is essential to the stabilization of the ionic complex, thus exhibiting the influence of this particular solvent in the very existence of the complex. In spite of the conclusion that CLE has higher affinity than CLC for Pb2+ and Cd2+ ions, only further studies in water solution will permit to evaluate the real potential of this molecule as an efficient scavenger of environmental heavy metal pollution.

This dissertation presents a numerical study using molecular dynamic simulations that interrogates the polymer structure as it is strained continuously in time and correlates it with the stress developed in it. We investigate the role of external control variables such as temperature, strain-rate, chain length, and density. At temperatures higher than glass transition, stress anisotropy is reduced even though bond stretch is greater at higher temperatures. There is a significant increase in stress level with increasing density. At faster rates of loading stress anisotropy increases. Deformation is mostly due to bond stretch and bond bending rather than overall shape and size. Stress levels increase with longer chain length. Cross-linkers beyond a critical value of functionality cause increased constraint on the motion of monomers and uniaxial stress developed increases. Stacking of chains also plays a dominant role in terms of excluded volume interactions. Low density, high temperature, low values of functionality of cross-linkers, and short chain length, facilitate chain uncoiling and chain slipping in crosslinked polymers. Uniaxial stress in linear polymers, on the other hand, is only mildly in uenced by temperature. Sinusoidal strain loading clearly reveals the viscoelastic nature of polymers. Internal structural parameters of the chains such as bond length, bond angle show hysteresis during loading and unloading. However, parameters representing overall size and shape of chains do not display any hysteresis. Small size magnetic particles and their small volume fractions in polymers show no signi cant e ect of applied external magnetic eld on anisotropic stress. Stress increases with lowering temperature, increasing density, decreasing volume fraction of magnetic particles, and increasing chain length

Au cours d’un traitement de surface de type dépôt assisté par plasma, les caractéristiques et propriétés de l’interface entre le dépôt et le substrat sont déterminées par la première couche atomique du dépôt, voire les premiers atomes qui commencent à recouvrir la surface du substrat. Aussi, la parfaite connaissance du comportement des particules incidentes et du réarrangement des atomes suite à l’impact d’une particule du plasma est-elle un élément essentiel à la description du comportement de la surface en cours de traitement et donc de ses propriétés ultérieures. Au cours de cette thèse, nous avons entrepris d’étudier, par une approche combinant expériences et simulation numérique par dynamique moléculaire, l’interaction d’espèces (C, Ti, W) avec une surface de silicium en fonction de paramètres tels que l’énergie, la fluence ou encore l’incidence des particules arrivant sur la surface. Une part importante de ce travail a consisté à adapter les codes de dynamique moléculaire (utilisation des champs de force réactifs) aux systèmes étudiés. La partie expérimentale a nécessité la mise en place de procédures spécifiques pour l’utilisation de l’équipement Storing Matter. Les résultats montrent que, quelles que soient l’espèce incidente, parmi celles étudiées, le coefficient de collage (SC) est dans la gamme [0.7 – 1] ; dans le cas de W, quasiment tous les atomes incidents restent sur la surface (SC~~1). Outre la détermination du coefficient de collage, pour différentes conditions initiales des espèces incidentes (énergie, incidence, fluence) les modifications apportées à la surface ont également été déterminées en termes d’implantation et de trajectoire dans le matériau des espèces incidentes, et de pulvérisation de la surface du substrat / During plasma assisted deposition, properties of the coating substrate interface depend on the first atomic layer of the deposit, or the atoms that first start to cover the surface. Therefore the good knowledge of the sticking coefficient and the reorganization of the surface following particle impact is an essential issue to achieve the description of the behavior of the processed surface and, therefore, its expected properties. Consequently, we investigated the interaction between incoming particles (C, Ti, W) and a silicon surface by using an approach combining molecular dynamic simulations and experiments. Various initial conditions were studied, energy, fluence and incidence angle of the incoming particles. An important part of this work has consisted in adapting the molecular dynamic codes (using reactive force fields) to the investigated systems. Meanwhile, experimental procedure specifically devoted to the use of the Storing Matter facility was also developed. Results show that the sticking coefficient (SC) value is in the range [0.7 – 1] irrespectively of the incoming species; in the case of W, almost all atoms stick on the surface (SC~~1). Besides the determination of sticking coefficient, the surface modification resulting from the particles impingement were determined for various initial conditions (energy, fluence, angle) in terms of implantation and displacement of the incoming species, and surface sputtering as well

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Ce travail de thèse ce concentre sur l’étude des protéines par l’usage de haute pression. Les articles présentés ici sont précéder d’une introduction présentant les différents modèles physiques utilisés pour décrire le repliement des protéines, une introduction posant les bases de la thermodynamique, ainsi que l’origine de la stabilité thermodynamique des protéines dans leur état plies. Il y a trois sujets principaux aborder dans ce mémoire. Le premier est l’étude de la coopérativité du repliement et du paysage de repliement de la protéine à répétition PP32 (Anp32a) a travers l’utilisation de la pression a différentes températures. La seconde étude concerne l’investigation de l’origine de l’expansivité thermique des protéines pliées grâce à l’utilisation de RMN haute pression et de la protéine très bien caractérisée Staphylococcal Nuclease (SNase) et de certaine de ses mutantes. Finalement, un dernier article sur la stabilité sous pression de la variant TC5b de la mini protéine model tryptophan-cage grâce une combinaison de RMN et de simulations moléculaires tout-atomes en « replica exchange ». / This thesis work focuses on the study of protein though the use of high pressure. There are three main points subject that are being inquired here. The first is the study of cooperativity and folding landscape of a repeat protein (Anp32a) though the use high pressure denaturation at different temperatures. The second concerns the investigation of the determinant of thermal expansivity in the folded state of protein using high pressure NMR, and the well characterized Staphylococcal Nuclease (SNase) and some of its mutants. Finally, a last article on the pressure stability of the model mini protein Tryptophan cage variant Tc5b by a combination of high pressure NMR and full atomic replica exchange simulations.

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.

<p dir="ltr">Increased scrutiny from customers and regulators to design aeroengines that are more efficient and environmentally friendly has pushed the need to investigate new engine architectures, manufacturing techniques, and computational fluid dynamic methods. This has led to the development of the CSTAR Gen. 2.5 centrifugal compressor, which uses an additively manufactured diffusion system and investigates the aerodynamic performance of an axi-centrifugal aeroengine. Additionally, an isolated unsteady diffuser computational model was previously developed that seeks to significantly reduce the computational cost of unsteady CFD in the diffuser.</p><p dir="ltr">The research presented in this paper is part of an ongoing attempt to utilize the capabilities of isolated unsteady diffuser modeling and rapid prototyping enabled through additive manufacturing in CSTAR Gen. 2.5 to develop a design framework that allows for quick computational and experimental analysis of diffusion systems in centrifugal compressors. Specifically, the scope of isolated unsteady diffuser modeling, which was previously only implemented in CSTAR Gen. 1 and at a single loading condition, is expanded by analyzing computational instabilities when applying the methodology to CSTAR Gen. 2.5 and analyzing results from four loading conditions (high loading, design point, low loading, and near choke) along a speedline.</p><p dir="ltr">Computational instabilities in the CSTAR Gen. 2.5 isolated diffuser models were determined to be caused by the decreased vaneless space compared to Gen. 1, which led to less “mixed” flow at the impeller outlet and a stronger diffuser potential field affecting the inlet profile. A boundary profile correction approach was developed which slightly increased very low total pressure near the diffuser shroud and negative radial velocity regions near the shroud and pitchwise locations of the diffuser vane leading edges while minimizing the overall affected area. The correction was successfully validated using 3D flow structure and minimum, average, and maximum total pressure, absolute velocity magnitude, and pressure comparisons at the diffuser inlet between an isolated and full-stage model.</p><p dir="ltr">Prediction capabilities of 3D flow structures and 1D performance parameters by isolated unsteady diffuser models were validated with results from full-stage unsteady models at each loading condition. The analysis indicated consistent performance by the isolated unsteady diffuser model at all loading conditions. An overall agreement in 3D flow structures was found, and trends in the full-stage unsteady models along the speedline were tracked well by the isolated unsteady model. At all loading conditions, there was a consistent over-representation of the separation region along the diffuser vane pressure side in the diffuser passage, overprediction of total pressure magnitude at the core of the flow at the diffuser outlet, and over- or underprediction of total pressure loss and static pressure recovery respectively. The similarity in the results between full-stage and isolated unsteady models, tracking of trends along the speedline, and consistent differences in 3D flow structure predictions and 1D performance parameters validates the isolated unsteady diffuser methodology for use at loading conditions from surge to choke.</p>

Volvo Construction Equipment (VCE) manufactures wheel loaders, articulated haulers, and excavators. By the end of 2030, the company hopes to have reduced the carbon footprint of its machines by 30 %. To increase energy efficiency and productivity, VCE is focused on developing futuristic wheel loaders that are both electric and autonomous. VCE has unveiled its latest autonomous wheel loader prototype called Zeux. This thesis work aims to create a simulation setup that includes a vehicle model of Zeux and a driver model that is optimised for the machine to complete a certain drive/load cycle. This simulation setup will be used to examine the machine’s performance, energy usage, and efficiency and compare it to a conventional machine to determine its advantages and limitations. The new vehicle model was created by modifying a conventional electric machine’s vehicle modeland a new four-wheel steering system was developed. A driver model was developed based on a condition-based decision tree and state machines with unique controllers for each driver input. This complete vehicle-driver simulation set-up has been tunedand optimised with respect to energy efficiency and productivity. The simulation results are then compared to the results of a similar conventional electric machine simulation model. According to the comparison study, the autonomous wheel loader concept has better productivity, lower hydraulic energy consumption as well as lower overall energy consumption compared to the conventional machine. It can complete the drive cycle much more efficiently despite having a similar powertrain and loading unit as the conventional machine. / Volvo Construction Equipment (VCE) tillverkar hjullastare, midjestyrda dumprar och grävmaskiner. I slutet av 2030 hoppas företaget ha minskat koldioxidavtrycket för sina maskiner med 30 %. För att öka energieffektiviteten och produktivitet är VCE fokuserade på att utveckla framtida hjullastare som både är elektriska och autonoma. VCE har presenterat sitt senaste autonoma hjullastarprototyp som heter Zeux. Detta examensarbete syftar till att skapa en simuleringsmiljö som innehåller en fordonsmodell av Zeux och en förarmodell som är optimerad för att maskinen ska klara en viss kör-/lastcykel. De framtagna modellerna ska sedan användas för att undersöka maskinens prestanda, energianvändning och effektivitet och jämföra resultaten med en konventionell elektrisk maskin för att fastställa dess fördelar och begränsningar. Den nya fordonsmodellen skapades genom att modifiera en konventionell elektrisk maskins fordonsmodell och ett nytt fyrhjulsstyrningssystem utvecklades. En förarmodell utvecklades baserad på ett tillståndsbaserat beslutsträd och tillståndsmaskiner med unika regulatorer för varje drivrutin. Den kompletta simuleringsmodellen har justerats och optimerats med avseende på energianvändning och produktivitet. Resultaten jämfördes sedan med simuleringsresultat av en liknande konventionell elektrisk hjullastare. Enligt jämförelsestudien, har konceptet med autonoma hjullastare bättre produktivitet, lägre hydrauliskenergiförbrukning samt lägre total energiförbrukning jämfört med den konventionella maskinen. Den kan slutföra körcykeln mycket mer effektivt samtidigt trots att den har en liknande drivlina och lastenhet som den konventionell maskin.

Representing more than 50% of a worldwide pharmaceutical market of US$ 400 billions, oral drug delivery systems become naturally the focus of many studies. For almost half a century scientists have attempted to develop a theoretical model capable of predicting oral drug absorption in humans. From steady state or quasi-equilibrium models to complex and computationally intractable dynamic modeling approaches, numerous research efforts tried to address the problem of interest. Surprisingly though, no simple insightful first-principle-based dynamic modeling approaches have been reported in the literature. It is the purpose of the present work to provide a simple dynamic distributed-parameter modeling approach for performance monitoring of oral drug delivery systems. As a consequence of the complexity of the gastrointestinal tract, drug oral bioavailability is influenced by many different parameters. These parameters range from the compound's physicochemical properties, the physiological factors of the environment to other factors inherent in the drug form itself known as encapsulation factors. Physicochemical properties account for parameters such as drug stability, solubility or diffusivity. Furthermore, the environment, namely the gastrointestinal tract, influences the drug delivery process to the body with its pH, intestinal transit time and the different transport mechanisms that take place. From a chemical engineering point of view, the human body's anatomy can be analyzed and conceptually realized as a transport-reaction chemical system. Within the proposed modeling framework, the stomach is modeled as a non-ideal continuous-stirred tank reactor (CSTR) and the small intestine is the place where convection-diffusion occurs. The governing transport equations have been solved at steady state conditions in a small intestine represented by the lumen surrounded by its wall. The present work however develops a systematic dynamic first-principle-based distributed-parameter modeling framework where the time-dependent convection-diffusion-reaction model equations are analytically solved, offering the concentration profile in the small intestine lumen and in the wall from the moment the drug is administered until the complete absorption or disintegration of the drug particles. Once the modeling work is performed, a thorough and insightful sensitivity analysis can be conducted in order to assess the impact of the different process parameters on drug bioavailability.