Molecular dynamics simulations of the liquid crystal phases of 2-(4-butyloxyphenyl)-5-octyloxypyrimidine (2PhP) and 5-(4-butyloxyphenyl)-2-octyloxy-pyrimidine (5PhP) are the focus of this thesis. The 2PhP and 5PhP mesogens display different liquid crystalline phase sequences, despite having very similar molecular structures. Specifically, both mesogens consist of aromatic phenyl and pyrimidine cores in between two flexible alkoxy tails, but they differ in the preferred core conformation. A multi-site coarse-grained model, in which the aromatic rings are represented by soft quadrupolar ellipsoids and the alkoxy chains are given a united atom representation, is proposed in this thesis. A parameterization route for the intra- and intermolecular potentials appropriate for liquid crystal simulations is developed. The ab initio based derivation of suitable molecular models for the two mesogens is discussed in detail, with particular emphasis on capturing proper phenyl-pyrimidine interactions which proved to be essential to correctly represent core-core interactions between neighboring molecules. A systematic determination of suitable Gay-Berne (GB) parameters has been adopted for the aromatic rings of 2PhP and 5PhP. To account for the pi-electron cloud below and above the ring plane, a quadrupole was added perpendicular to the ring. In the end, four parameterizations for aromatic rings have been selected for the simulations. Model characterization via pair interactions proved to be valuable in identifying and analyzing the short range structure in the phases. Extensive molecular dynamics simulations of these fluids at various temperatures are performed. Intermolecular structure and order, in aromatic core and the flexible tail regions, are analyzed. Intermolecular structure is divided into contributions parallel and perpendicular to the layers, as indicated by a layer normal or by a director, to differentiate smectic A (SmA) from smectic C (SmC). The presence of a ring quadrupole in the molecular model is shown to be essential to the correct reproduction of the experimentally observed phases. Simulations correctly indicate phases in agreement with experiment: SmC and SmA phases for 2PhP, and only a SmA phase for 5PhP. / Thesis (Ph.D, Chemistry) -- Queen's University, 2009-10-27 20:23:37.89

By developing strong, self-sustaining individuals in organisations, employees will need to withstand the forces of stressors and be able to cope with continuous changes within their working environment. To move the equilibrium level from the current to the desired condition, the field of forces must be altered - by adding driving forces and by removing restraining forces. An individual's sense of coherence may either alleviate or aggravate reactions to a stressor and moderate the impact of occupational stressors on the individual's affective outcomes. The objectives of this study were to validate the 13-item version of the Orientation to Life Questionnaire (OLQ) (Antonovsky, 1987) and to determine the experience of employees with high levels of sense of coherence regarding helping and restraining factors within the workplace (compared to that of those with a low sense of coherence). A cross-sectional s w e y design was used. The total population (N = 2 678) of employees in a financial institution in Gauteng was used in this study. Random samples of groups with a strong (n = 300) and low (n = 300) sense of coherence were taken for purposes of the qualitative study. The OLQ (Antonovsky, 1987) and a biographical questionnaire were administered. The scale showed acceptable reliability and construct validity. The study set out to determine the applicability of the theoretical model of sense of coherence to employees in a financial institution. Reliability analysis revealed that the three subscales of sense of coherence were sufficiently internally consistent. The reliability of the measuring instrument were assessed with the use of Cronbach alpha coefficients. Descriptive statistics (e.g. mean and standard deviations) were used to analyse the data. By using the structural equation modelling approach, a one-dimensional factor structure for sense of coherence amongst employees in a financial institution emerged. The reliability analysis revealed that the alpha scores were acceptable. It can therefore be concluded that the 13-item version of the OLQ is a reliable and valid measuring instrument. The results showed that although employee groups with high and low levels of sense of coherence are experiencing similar helping and restraining factors within their working environment, helping factors are being experienced with a higher frequency by groups with high levels of sense of coherence and restraining factors with a higher frequency by groups with low levels of sense of coherence. Recommendations were made for future research. / Thesis (M.A. (Industrial Psychology))--North-West University, Potchefstroom Campus, 2007

Molecular modeling has come a long way during the past decades and in the current thesis modeling of biological membranes is the focus. The main method of choice has been classical Molecular Dynamics simulations and for this technique a model Hamiltonian, or force field (FF), has been developed for lipids to be used for biological membranes. Further, ways of more accurately simulate the interactions between solutes and membranes have been investigated. A FF coined Slipids was developed and validated against a range of experimental data (Papers I-III). Several structural properties such as area per lipid, scattering form factors and NMR order parameters obtained from the simulations are in good agreement with available experimental data. Further, the compatibility of Slipids with amino acid FFs was proven. This, together with the wide range of lipids that can be studied, makes Slipids an ideal candidate for large-scale studies of biologically relevant systems. A solute's electron distribution is changed as it is transferred from water to a bilayer, a phenomena that cannot be fully captured with fixed-charge FFs.  In Paper IV we propose a scheme of implicitly including these effects with fixed-charge FFs in order to more realistically model water-membrane partitioning. The results are in good agreement with experiments in terms of free energies and further the differences between using this scheme and the more traditional approach were highlighted. The free energy landscape (FEL) of solutes embedded in a model membrane is explored in Paper V. This was done using biased sampling methods with a reaction coordinate that included intramolecular degrees of freedom (DoF). These DoFs were identified in different bulk liquids and then used in studies with bilayers. The FELs describe the conformational changes necessary for the system to follow the lowest free energy path. Besides this, the pitfalls of using a one-dimensional reaction coordinate are highlighted.

The detrimental effects of rising CO₂ levels on the global climate have made carbon abatement technologies one of the most widely researched areas of recent times. In this thesis, we first present a techno-economic analysis of a novel approach to directly capture CO₂ from air (Air Capture) using highly selective adsorbents. Our process modeling calculations suggest that the monetary cost of Air Capture can be reduced significantly by identifying adsorbents that have high capacities and optimum heats of adsorption. The search for the best performing material is not limited to Air Capture, but is generally applicable for any adsorption-based separation. Recently, a new class of nanoporous materials, Metal-Organic Frameworks (MOFs), have been widely studied using both experimental and computational techniques. In this thesis, we use a combined quantum chemistry and classical simulations approach to predict macroscopic properties of MOFs. Specifically, we describe a systematic procedure for developing classical force fields that accurately represent hydrocarbon interactions with the MIL-series of MOFs using Density Functional Theory (DFT) calculations. We show that this force field development technique is easily extended for screening a large number of complex open metal site MOFs for various olefin/paraffin separations. Finally, we demonstrate the capability of DFT for predicting MOF topologies by studying the effect of ligand functionalization during CuBTC synthesis. This thesis highlights the versatility and opportunities of using multiscale modeling approach that combines process modeling, classical simulations and quantum chemistry calculations to study nanoporous materials for adsorptive separations.

Simulações de Dinâmica Molecular tornaram-se uma ferramenta indispensável no estudo de sistemas em fase condensada, incluindo sistemas líquido-Cristalinos, e na predição de propriedades dinâmicas. Cristais líquidos possuem um leque enorme de aplicações, mas o estudo teórico destes sistemas torna-se complicado devido ao seu tamanho, ao método utilizado para obtenção dos parâmetros do campo de força e, principalmente, à transferibilidade dos parâmetros para outro estado termodinâmico. Tendo isso em vista, este trabalho propõe uma metodologia para parametrizar campos de força derivados de cálculos mecânico-quânticos que possuam um grau de transferibilidade confiável. O sistema escolhido neste trabalho foi o 4’-Pentil- 4-Carbonitrila, também conhecido como 5CB, pois o mesmo já é utilizado em diversos aparelhos óptico-eletrônicos; a parametrização intramolecular foi feita com o programa JOYCE, e a intermolecular, com o programa PICKY. Os parâmetros intramoleculares obtidos mostraram uma boa descrição da geometria interna do sistema, contribuindo para a parametrização intermolecular, a qual obteve uma excelente descrição de propriedades termodinâmicas. Este trabalho corrobora para a hipótese de que campos de força derivados de cálculos mecânico- quânticos podem descrever diferentes fases termodinâmicas com um alto grau de confiabilidade. / Simulations using Molecular dynamics have become a powerful tool in the study of systems in condensed phase, including liquid-crystalline systems, and in the prediction of dynamical properties. Liquid Crystals have many applications, but the theoretical study of these systems is more complex because of their size, the method that was used in the force field parametrization and, mainly, because in most of the cases parameters cannot be transferred to another thermodynamical state. With that in mind, this work propose a methodology to parametrize force fields derived from quantummechanical calculations and which can be transferred to other thermodynamical state without losing important information. The chosen system in this work was the 4-Cyano-4’-Pentylbiphenyl, also known as 5CB, which have been used in many optical-electronic device and the intramolecular parametrization was done with the JOYCE program and the program PICKY was used in the intermolecular parametrization. The intramolecular parameters obtained show a good description of the internal geometry, contributes to the intermolecular parametrization, with we obtained an accurate description of the thermodynamical and physical chemical properties. This work corroborate to the hypothesis that force field derived from quantum-mechanical calculations can describe different thermodynamical states without losing important information.

Métodos computacionais assumiram a partir de 1980, um papel de destaque no planejamento de novos fármacos, oferecendo abordagens racionais para reduzir o grau de incerteza na geração de novos compostos bioativos. Dentre estes métodos, destacam-se aqueles dependentes de campos de força, como o atracamento e a dinâmica molecular. Infelizmente, estes métodos exigem estratégias de parametrização capazes de lidar com a diversidade química associada ao planejamento de fármacos. Os esforços atuais neste sentido são focados em fase gasosa, como no caso do GAFF e MMFF94, Assim, o presente trabalho busca explorar a capacidade de um campo de força baseado em fase condensada, o GROMOS, na reprodução de propriedades fisico-químicas de anéis aromáticos comumente encontrados em fármacos. Assim, parâmetros ligados e de Lennard-Jones do GROMOS53a6 foram utilizados para a construção das topologias destas moléculas orgânicas, enquanto novos parâmetros coulômbicos e torsionais foram gerados. Em seguida, suas propriedades físico-químicas foram simuladas e comparadas aos respectivos valores experimentais, permitindo a determinação da qualidade de cada topologia. Até o momento, 41 moléculas foram parametrizadas com sucesso, levando a erros absolutos abaixo de 15% para densidade, entalpia de vaporização e capacidade térmica isobárica. A partir desta etapa de validação, os parâmetros obtidos foram aplicados no estudo de hexafirinas sintéticas em diferentes solventes e íons, acessando com sucesso a conformação e coordenação das moléculas envolvidas. Desta forma, os dados obtidos constituem-se em um benchmark para futuros estudos baseados no campo de força GROMOS, sugerindo seu potencial para estudos de moléculas orgânicas sintéticas em fase condensada. Abre-se, ainda, a perspectiva de emprego de técnicas de dinâmica molecular, com estes parâmetros, no estudo do perfil conformacional, dinâmica e flexibilidade de fármacos em solução. / Since 1980, computational methods took a major role in drug design, offering rational approaches to mitigate the uncertainty in the generation of new bioactive compounds. Among these methods, it is possible to highlight the force field dependents, like molecular docking and molecular dynamics. Unfortunately, these methods demand parametrization strategies capable to to deal with such chemical diversity associated with drug planning. The efforts currently available in this sense are focused on gas phase, like GAFF and MMF94, Therefore, the present work aims to explore the capacity of a force field based on condensed phase, GROMOS, on reproducing physical-chemical properties of aromatic rings commonly found on drugs. Thus, bonded and Lennard-Jones parameters of GROMOS53a6 was used to build topologies for these organic molecules, while new coulombic and torsional parameters were generated. Next, their physical-chemical properties were simulated and compared to respective experimental data, allowing a quality determination of each topology. So far, 41 molecules were successfully parameterized, leading to absolute errors below 15% for density, enthalpy of vaporization and isobaric heat capacity. From this validation step, the obtained parameters were applied on the synthetic hexaphyrin studies in different solvents and ions, successfully accessing the conformation and coordination of the participating molecules. Therefore, the obtained data constitute a benchmark for future studies based on GROMOS force field, suggesting its potential to carry out studies on synthetic organic molecules in condensed phase. Yet, it opens the perspective of applying molecular dynamics techniques with these parameters on the study of conformational profile, dynamics and flexibility of drugs in solution.

Chalconas e flavonoides são compostos comumente presentes em plantas, e constituem uma grande família de produtos naturais com um amplo espectro de atividades farmacológicas. Mudanças na estrutura destas moléculas tem se provado úteis no desenvolvimento de novos agentes terapêuticos, sendo assim, esses compostos tem sido intensamente estudados. Métodos computacionais como a dinâmica molecular (DM) são ferramentas poderosas para o acesso a informações de difícil obtenção por outros meios experimentais. Campos de força acurados são essenciais para a descrição de sistemas biológicos em simulações de DM, assim, um conjunto de parâmetros associado a um composto necessita ser cuidadosamente calibrado para garantir a obtenção de resultados confiáveis. Considerando a relevância dessa família de moléculas e a falta de parâmetros validados para a estrutura básica de chalconas e flavonoides no campo de força GROMOS, o presente trabalho tem como objetivo prover um novo conjunto de parâmetros para a simulação destes compostos. Um protocolo que combina cálculos ab initio e simulações de DM foi aplicado para obter novas cargas atômicas e parâmetros torsionais Propriedades experimentais como densidade e entalpia de vaporização foram usadas como comparação aos valores obtidos em simulações, como forma de validação dos parâmetros. A comparação dos perfis torsionais obtidos por cálculos quânticos e por mecânica molecular auxiliou na geração de novos potenciais que permitem uma descrição conformacional mais acurada dos diedros de interesse. Diversos ajustes em grupos de cargas foram feitos, e os valores para propriedades termodinâmicas obtidos nas simulações estão em concordância com os dados experimentais. Simulações de metadinâmica foram realizadas para avaliar o comportamento conformacional de chalconas e flavonoides completos, e contatos de NOE foram medidos durante simulações de DM, obtendo uma reprodução quase completa das distâncias entre alguns grupos de prótons. O protocolo empregado gerou parâmetros de campo de força que reproduzem bem dados experimentais, e espera-se que estes resultados contribuam para a realização de estudos computacionais acurados envolvendo chalconas e flavonoides. / Chalcones and flavonoids are polyphenolic compounds extensively distributed in plants, constituting a large family of natural products with a broad spectrum of pharmacological activities. Changes in their structure have been proven useful for the development of new therapeutic agents, thus these biomolecules are being intensively studied and modified. Computational methods such as molecular dynamics (MD) simulations are powerful tools to assess information that is difficult to obtain experimentally. Accurate force fields are essential for describing biological systems in a MD simulation, thus a parameter set associated to a certain compound need to be carefully calibrated to ensure reliable results. Considering the relevance of this family of molecules and the lack of validated parameters for the basic structure of chalcones and flavonoids in the GROMOS force field, this work intends to provide a new parameter set for the simulation of these compounds. We employed a protocol combining ab initio calculations and MD simulations for the obtention of new atomic charges and torsional parameters Experimental properties such as density and enthalpy of vaporization were compared to the calculated values in order to validate the parameters. A fitting of molecular-mechanical to quantum-mechanical torsional profiles was performed for each of the dihedrals of interest in the structures, generating new torsional potentials that provide accurate description of conformational behavior. Additionally, adjustments in charge groups were made in topologies used for the MD simulations and the obtained values of the thermodynamic properties are in good agreement with experimental data. Metadynamics simulations were performed to evaluate the conformation of complete chalcones and flavonoids, and NOE contacts during MD simulations were measured, obtaining an almost complete reproduction of inter-proton interactions. The employed protocol generated force field parameters that reproduce well the target data and we expect they will contribute to more accurate computational studies on the biological role of chalcones and flavonoids.

Métodos computacionais assumiram a partir de 1980, um papel de destaque no planejamento de novos fármacos, oferecendo abordagens racionais para reduzir o grau de incerteza na geração de novos compostos bioativos. Dentre estes métodos, destacam-se aqueles dependentes de campos de força, como o atracamento e a dinâmica molecular. Infelizmente, estes métodos exigem estratégias de parametrização capazes de lidar com a diversidade química associada ao planejamento de fármacos. Os esforços atuais neste sentido são focados em fase gasosa, como no caso do GAFF e MMFF94, Assim, o presente trabalho busca explorar a capacidade de um campo de força baseado em fase condensada, o GROMOS, na reprodução de propriedades fisico-químicas de anéis aromáticos comumente encontrados em fármacos. Assim, parâmetros ligados e de Lennard-Jones do GROMOS53a6 foram utilizados para a construção das topologias destas moléculas orgânicas, enquanto novos parâmetros coulômbicos e torsionais foram gerados. Em seguida, suas propriedades físico-químicas foram simuladas e comparadas aos respectivos valores experimentais, permitindo a determinação da qualidade de cada topologia. Até o momento, 41 moléculas foram parametrizadas com sucesso, levando a erros absolutos abaixo de 15% para densidade, entalpia de vaporização e capacidade térmica isobárica. A partir desta etapa de validação, os parâmetros obtidos foram aplicados no estudo de hexafirinas sintéticas em diferentes solventes e íons, acessando com sucesso a conformação e coordenação das moléculas envolvidas. Desta forma, os dados obtidos constituem-se em um benchmark para futuros estudos baseados no campo de força GROMOS, sugerindo seu potencial para estudos de moléculas orgânicas sintéticas em fase condensada. Abre-se, ainda, a perspectiva de emprego de técnicas de dinâmica molecular, com estes parâmetros, no estudo do perfil conformacional, dinâmica e flexibilidade de fármacos em solução. / Since 1980, computational methods took a major role in drug design, offering rational approaches to mitigate the uncertainty in the generation of new bioactive compounds. Among these methods, it is possible to highlight the force field dependents, like molecular docking and molecular dynamics. Unfortunately, these methods demand parametrization strategies capable to to deal with such chemical diversity associated with drug planning. The efforts currently available in this sense are focused on gas phase, like GAFF and MMF94, Therefore, the present work aims to explore the capacity of a force field based on condensed phase, GROMOS, on reproducing physical-chemical properties of aromatic rings commonly found on drugs. Thus, bonded and Lennard-Jones parameters of GROMOS53a6 was used to build topologies for these organic molecules, while new coulombic and torsional parameters were generated. Next, their physical-chemical properties were simulated and compared to respective experimental data, allowing a quality determination of each topology. So far, 41 molecules were successfully parameterized, leading to absolute errors below 15% for density, enthalpy of vaporization and isobaric heat capacity. From this validation step, the obtained parameters were applied on the synthetic hexaphyrin studies in different solvents and ions, successfully accessing the conformation and coordination of the participating molecules. Therefore, the obtained data constitute a benchmark for future studies based on GROMOS force field, suggesting its potential to carry out studies on synthetic organic molecules in condensed phase. Yet, it opens the perspective of applying molecular dynamics techniques with these parameters on the study of conformational profile, dynamics and flexibility of drugs in solution.

Simulações de Dinâmica Molecular tornaram-se uma ferramenta indispensável no estudo de sistemas em fase condensada, incluindo sistemas líquido-Cristalinos, e na predição de propriedades dinâmicas. Cristais líquidos possuem um leque enorme de aplicações, mas o estudo teórico destes sistemas torna-se complicado devido ao seu tamanho, ao método utilizado para obtenção dos parâmetros do campo de força e, principalmente, à transferibilidade dos parâmetros para outro estado termodinâmico. Tendo isso em vista, este trabalho propõe uma metodologia para parametrizar campos de força derivados de cálculos mecânico-quânticos que possuam um grau de transferibilidade confiável. O sistema escolhido neste trabalho foi o 4’-Pentil- 4-Carbonitrila, também conhecido como 5CB, pois o mesmo já é utilizado em diversos aparelhos óptico-eletrônicos; a parametrização intramolecular foi feita com o programa JOYCE, e a intermolecular, com o programa PICKY. Os parâmetros intramoleculares obtidos mostraram uma boa descrição da geometria interna do sistema, contribuindo para a parametrização intermolecular, a qual obteve uma excelente descrição de propriedades termodinâmicas. Este trabalho corrobora para a hipótese de que campos de força derivados de cálculos mecânico- quânticos podem descrever diferentes fases termodinâmicas com um alto grau de confiabilidade. / Simulations using Molecular dynamics have become a powerful tool in the study of systems in condensed phase, including liquid-crystalline systems, and in the prediction of dynamical properties. Liquid Crystals have many applications, but the theoretical study of these systems is more complex because of their size, the method that was used in the force field parametrization and, mainly, because in most of the cases parameters cannot be transferred to another thermodynamical state. With that in mind, this work propose a methodology to parametrize force fields derived from quantummechanical calculations and which can be transferred to other thermodynamical state without losing important information. The chosen system in this work was the 4-Cyano-4’-Pentylbiphenyl, also known as 5CB, which have been used in many optical-electronic device and the intramolecular parametrization was done with the JOYCE program and the program PICKY was used in the intermolecular parametrization. The intramolecular parameters obtained show a good description of the internal geometry, contributes to the intermolecular parametrization, with we obtained an accurate description of the thermodynamical and physical chemical properties. This work corroborate to the hypothesis that force field derived from quantum-mechanical calculations can describe different thermodynamical states without losing important information.

Chalconas e flavonoides são compostos comumente presentes em plantas, e constituem uma grande família de produtos naturais com um amplo espectro de atividades farmacológicas. Mudanças na estrutura destas moléculas tem se provado úteis no desenvolvimento de novos agentes terapêuticos, sendo assim, esses compostos tem sido intensamente estudados. Métodos computacionais como a dinâmica molecular (DM) são ferramentas poderosas para o acesso a informações de difícil obtenção por outros meios experimentais. Campos de força acurados são essenciais para a descrição de sistemas biológicos em simulações de DM, assim, um conjunto de parâmetros associado a um composto necessita ser cuidadosamente calibrado para garantir a obtenção de resultados confiáveis. Considerando a relevância dessa família de moléculas e a falta de parâmetros validados para a estrutura básica de chalconas e flavonoides no campo de força GROMOS, o presente trabalho tem como objetivo prover um novo conjunto de parâmetros para a simulação destes compostos. Um protocolo que combina cálculos ab initio e simulações de DM foi aplicado para obter novas cargas atômicas e parâmetros torsionais Propriedades experimentais como densidade e entalpia de vaporização foram usadas como comparação aos valores obtidos em simulações, como forma de validação dos parâmetros. A comparação dos perfis torsionais obtidos por cálculos quânticos e por mecânica molecular auxiliou na geração de novos potenciais que permitem uma descrição conformacional mais acurada dos diedros de interesse. Diversos ajustes em grupos de cargas foram feitos, e os valores para propriedades termodinâmicas obtidos nas simulações estão em concordância com os dados experimentais. Simulações de metadinâmica foram realizadas para avaliar o comportamento conformacional de chalconas e flavonoides completos, e contatos de NOE foram medidos durante simulações de DM, obtendo uma reprodução quase completa das distâncias entre alguns grupos de prótons. O protocolo empregado gerou parâmetros de campo de força que reproduzem bem dados experimentais, e espera-se que estes resultados contribuam para a realização de estudos computacionais acurados envolvendo chalconas e flavonoides. / Chalcones and flavonoids are polyphenolic compounds extensively distributed in plants, constituting a large family of natural products with a broad spectrum of pharmacological activities. Changes in their structure have been proven useful for the development of new therapeutic agents, thus these biomolecules are being intensively studied and modified. Computational methods such as molecular dynamics (MD) simulations are powerful tools to assess information that is difficult to obtain experimentally. Accurate force fields are essential for describing biological systems in a MD simulation, thus a parameter set associated to a certain compound need to be carefully calibrated to ensure reliable results. Considering the relevance of this family of molecules and the lack of validated parameters for the basic structure of chalcones and flavonoids in the GROMOS force field, this work intends to provide a new parameter set for the simulation of these compounds. We employed a protocol combining ab initio calculations and MD simulations for the obtention of new atomic charges and torsional parameters Experimental properties such as density and enthalpy of vaporization were compared to the calculated values in order to validate the parameters. A fitting of molecular-mechanical to quantum-mechanical torsional profiles was performed for each of the dihedrals of interest in the structures, generating new torsional potentials that provide accurate description of conformational behavior. Additionally, adjustments in charge groups were made in topologies used for the MD simulations and the obtained values of the thermodynamic properties are in good agreement with experimental data. Metadynamics simulations were performed to evaluate the conformation of complete chalcones and flavonoids, and NOE contacts during MD simulations were measured, obtaining an almost complete reproduction of inter-proton interactions. The employed protocol generated force field parameters that reproduce well the target data and we expect they will contribute to more accurate computational studies on the biological role of chalcones and flavonoids.