In this work, the development of parameters for a series of imidazolium-based ionic liquids molecules, now included in the AMOEBA force field, is discussed. The quality of obtained parameters is tested in a variety of calculations to reproduce structural, thermodynamic, and transport properties. First, it is proposed a novel method to parameterize in a faster, and more efficient way parameters for the AMOEBA force field that can be applied to any imidazolim-based cation. Second, AMOEBA-IL polarizable force field is applied to study the N-tert-butyloxycarbonylation of aniline reaction mechanism in water/[EMIM][BF4] solvent via QM/MM approach and compared with the reaction carried out in gas-phase and implicit solvent media. Third, AMOEBA-IL force field is applied in alchemical calculations. Free energies of solvation for selected solutes solvated in [EMIm][OTf] are calculated via BAR method implemented in TINKER considering the effect of polarization as well as the methodology to perform the sampling of the alchemical process. Finally, QM/MM calculations using AMOEBA to get more insights into the catalytic reaction mechanism of horseradish peroxidase enzyme, particularly the structures involved in the transition from Cp I to Cp II.

Ce mémoire présente une méthodologie théorique pour comprendre l'origine de différence de comportement dynamique de complexes alkylidènes, catalyseurs de type Schrock de la métathèse des oléfines, greffés un support de silice amorphe. Dans un travail antérieur, les différences entre les valeurs de l'anisotropie de déplacement chimique (CSA) obtenus par des mesures de RMN du solide et celles estimées par le calcul pour des systèmes figés avaient conduit à suggérer des régimes dynamiques différents pour ces complexes, certains étant proposés comme immobiles, d'autres comme mobiles. Dans le premier groupe se trouve les complexes du molybdène et dans le second les complexes du tungstène, rhénium et tantale. Dans le cadre de cette thèse, nous nous sommes donc attachés à mettre en place une méthodologie pour déterminer ces CSA et donc la nature de la dynamique de chaque système qui conduit au CSA moyenné. Nous nous sommes d'abord intéressés à des systèmes moléculaires pour révéler des interactions non covalentes entre les complexes et le support silice à partir d'une approche de type petit cluster en utilisant divers niveaux de calculs DFT et modèles moléculaires. Cette modélisation moléculaire de la silice étant insuffisante, nous avons entrepris une modélisation de la surface de silice amorphe par dynamique moléculaire classique dont les caractéristiques ont été comparées aux données expérimentales existantes. Le comportement dynamique de ces systèmes greffés sur silice amorphe a été simulé par dynamique moléculaire ab initio QM/MM, couplant une description quantique du complexe organométallique à une description classique du support. Ces études dynamiques ont conduit à des valeurs de CSA moyennées dans le temps de la dynamique. La comparaison de ces valeurs calculées et des valeurs expérimentales a permis d'apporter des éléments de réponse sur l'origine des différences de comportement dynamique de ces complexes alkylidènes. De façon remarquable des mouvements d'ensemble des espèces greffées par rapport à la surface de silice et des modifications de la coordination du métal par l'apparition d'interaction agostique contribuent à moyenner le CSA. / This work presents a theoretical study aimed at analyzing the origin of the differences in the dynamics of alkylidenes complexes, known as Schrock olefin metathesis catalysts, supported on amorphous silica. The difference between the experimental chemical shift anisotropies (CSA) obtained from solid state NMR measurements and the values computed for the most stable configurations have been used in previous work to suggest different dynamical behaviors for the supported complexes. Some of the complexes were suggested to have limited mobilities while others were suggested to be mobiles. In the first group, one finds Mo complexes, and in the second, W, Re and Ta complexes. In this thesis, a methodology was established to compute the CSA and to obtain information on the dynamics that average the CSA over time. In the first part of this work, molecular species were considered and the non covalent interactions between the surface and the grafted complexes were studied with various DFT levels of calculations and various molecular models. This molecular modeling being inappropriate, a better representation of the surface of amorphous silica was carried out with classical molecular dynamic methods. The nature of the surface was analyzed and compared with available experimental information. In a following step, the dynamic behavior of these complexes was determined using anab initio molecular dynamics (QM/MM) approach in which the metal fragments are treated at the quantum level and the support represented in a classical manner. These molecular dynamics studies yield time averaged CSA that are reasonably close to the experimental values and confirm in particular the partition into immobile (Mo) and mobile (W, Re, Ta) complexes. A detailed analysis of the results leads to a better understanding of the nature of the dynamics. Remarkably, motions relative to the silica surface and vibrations influencing the coordination sphere of the metal involving in particular agostic interactions both contribute to average the CSA.

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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Ce travail se situe dans le contexte de la chimie des organolithiens, qui a fait l’objet de nombreuses études théoriques et expérimentales pendant ces dernières années. Il concerne plus particulièrement l’étude de la structure et de la réactivité des systèmes superbasiques monométalliques lithiés à l’aide de différents outils de la chimie théorique. Dans un premier temps, la dynamique moléculaire et les méthodes mixtes QM/MM ont été utilisées pour modéliser l’effet d’un solvant coordinant sur les différents types d’agrégats. Ensuite, le rôle de la solvatation sur la contribution entropique et enthalpique à l’énergie libre des agrégats n-BuLi, LiPM (LiPM= (S)-N-méthyle-2-pyrrolidine méthylate de lithium) et des agrégats mixtes n-BuLi / LiPM a été discuté en détail. Enfin, nous avons réalisé quelques calculs d’états de transition qui ont permis de discuter les mécanismes réactionnels possibles lors de la réaction de la 2-chloropyridine avec la superbase n-BuLi / LiPM dans différents solvants. / In this work, we report computational investigation intended to get a deeper insight on the structure and reactivity of organolithium compounds and the role of solvent on aggregation. Briefly, we have investigated : (1) The structure and the dynamics of simple aggregates in ethereal solvents. (2) The structure of n-BuLi, LiPM and mixed n-BuLi/LiPM aggregates in gas phase, hexane and THF. (3) The reaction mechanisms of n-BuLi/LiPM aggregates with pyridine making a comparison between the reaction rates for a-, ortho-metallation and nucleophilic addition. Several solvent models have been used. Molecular Dynamics simulations have been carried out using a previously developed QM/MM approach. Quantum mechanical calculations have been carried out at density functional theory and ab initio levels.

Usando as Regras de Soma da QCD, testamos se a nova estrutura estreita, X(4350) recentemente observada pela Colaboração Belle, pode ser descrita como um estado molecular D8D80 exótico JPC = 1+. Consideramos as contribuições dos condensados de dimensão oito, trabalhamos com os termos dominantes em 8 mantendo os termos lineares na massa do quark estranho m8. A massa obtida é igual a mD8D80 = (5.05±0.19) GeV. Consideramos também uma corrente molecular 1+, DD0 e obtemos mDD0 = (4.92 ± 0.08) GeV. Concluímos que não é possível descrever a estrutura X(4350) como um estado molecular 1+ D8D80. / Using the QCD sum rules we test if the new narrow structure, the X(4350) recently observed by the Belle Collaboration, can be described as a JPC = 1+ exotic D8D80 molecular state. We consider the contributions of condensates up to dimension eight, we work at leading order in s and we keep terms which are linear in the strange quark mass ms. The mass obtained for such state is mD8D80 =(5.05 ± 0.19) GeV. We also consider a molecular 1+, DD0 current and we obtain mDD0 = (4.92 ± 0.08) GeV. We conclude that it is not possible to describe the X(4350) structure as a 1+ D8D80 molecular state.

In obesity, lipids stored in muscle as lipid droplets (LDs) lead to accumulation of fatty acid (FA) metabolites and insulin resistance. This research involves development of immunofluorescence microscopy methods to generate novel information on the subcellular content and distribution of key enzymes that play a role in the underlying mechanisms. Chapters 3 and 4 describe visualisation of two lipid synthesising enzymes. Both are more abundant in type I muscle fibres. Chapter 5 reveals no differences between these enzymes in non obese and obese elderly women. Chapter 6 reveals that a key lipolytic enzyme (ATGL) has a higher content in type I fibres, but its activator does not. Chapter 7 describes visualisation of SNAP23 and reveals a high content at the plasma membrane and mitochondria and low content in LDs. Chapter 8 fails to observe a difference between obese and non obese elderly women in plasma membrane SNAP23, and therefore fails to confirm the hypothesis that LDs hijack SNAP23. However, obese women have less SNAP23 in mitochondria and this may limit FA oxidation. In conclusion this thesis describes several novel mechanisms by which obesity leads to accumulation of FA metabolites and insulin resistance. The developed methods will be a valuable novel tool for future diabetes research.

<div>Computational Chemistry has proven to be an effective means of solving chemical problems. The two main tools of Computational Chemistry - quantum mechanics and molecular mechanics, have provided viable avenues to probe such chemical problems at an electronic or molecular level, with varying levels of accuracy and speed. In this work, attempts have been made to combine the speed of molecular mechanics and the accuracy of quantum mechanics to work across multiples scales of time and length, effectively resulting in simulations of large chemical systems without compromising the accuracy.</div><div><br></div><div>The primary tool utilized for methods development and application in this work is the Effective Fragment Potential (EFP) method. The EFP method is a computational technique for studying non-covalent interactions in complex systems. EFP is an accurate \textit{ab initio} force field, with accuracy comparable to many Density Functional Theory (DFT) methods, at significantly lower computational cost. EFP decomposes intermolecular interactions into contributions from four terms: electrostatics, polarization, exchange-repulsion and dispersion.</div><div><br></div><div>In the first chapter, the possibility of applying EFP method to study large radical-water clusters is probed. An approximate theoretical model in which the transition dipole moments of excitations are computed using the information from the ground state orbitals is implemented.</div><div><br></div><div>A major challenge to broaden the scope of EFP is to overcome its limitation in describing only small and rigid molecules such as water, acetone, etc. In the second chapter, the extension of EFP method to large covalently bound biomolecules and polymers such as proteins, lipids etc., is described. Using this new method, referred to as BioEFP/mEFP, it is shown that the effect of polarization is non-negligible and must be accounted for when modeling photochemical and electron-transfer processes in photoactive proteins.</div><div><br></div><div>Another area of interest is the development of novel drug-target binding models, in which a chemically active part of the ligand is modified via functional group modification, while the rest of the system remains intact. In the third chapter, the development and application of a drug-target binding model is explained.<br></div><div><br></div><div><div>Lastly, in the fourth and final chapter, we show the derivation for working equations corresponding to the coupling gradient term describing the dispersion interactions between quantum mechanical and effective fragment potential regions.</div><div><br></div><div>The primary focus of this work is to explore and expand the boundaries of multiscale QM/MM simulations applied to chemical and biomolecular systems. We believe that the work described here leads to exciting pathways in the future in terms of modeling novel systems and processes such as heterogeneous catalysis, QSAR, crystal structure prediction, etc.</div></div>

Usando as Regras de Soma da QCD, testamos se a nova estrutura estreita, X(4350) recentemente observada pela Colaboração Belle, pode ser descrita como um estado molecular D8D80 exótico JPC = 1+. Consideramos as contribuições dos condensados de dimensão oito, trabalhamos com os termos dominantes em 8 mantendo os termos lineares na massa do quark estranho m8. A massa obtida é igual a mD8D80 = (5.05±0.19) GeV. Consideramos também uma corrente molecular 1+, DD0 e obtemos mDD0 = (4.92 ± 0.08) GeV. Concluímos que não é possível descrever a estrutura X(4350) como um estado molecular 1+ D8D80. / Using the QCD sum rules we test if the new narrow structure, the X(4350) recently observed by the Belle Collaboration, can be described as a JPC = 1+ exotic D8D80 molecular state. We consider the contributions of condensates up to dimension eight, we work at leading order in s and we keep terms which are linear in the strange quark mass ms. The mass obtained for such state is mD8D80 =(5.05 ± 0.19) GeV. We also consider a molecular 1+, DD0 current and we obtain mDD0 = (4.92 ± 0.08) GeV. We conclude that it is not possible to describe the X(4350) structure as a 1+ D8D80 molecular state.

Hepatitis C Virus (HCV) is a global health problem, with over 170 million infected individuals worldwide. 70-80% of infected individuals develop progressive disease, and approximately 2% of these acquire hepatocellular carcinoma (HCC). HCV entry is dependent on tetraspanin CD81, scavenger receptor BI, and tight junction proteins claudin-1 and occludin. Tetraspanins are involved in multiple biological functions including cell-ECM adhesion and motility. An actin polymerization-dependent cell spread was observed upon ligation of CD81 on hepatoma cells. Importantly, HCV infection perturbed CD81-dependent cell spread, suggesting HCV infection may modulate CD81 function in hepatoma cells. Functional assays demonstrated that CD81 expression and HCV infection promote hepatoma cell motility. These findings allude to a link between HCV infection and associated HCC development. Establishment of a chronic infection demonstrates that HCV can escape from the host adaptive immune responses. We developed an in vitro cell culture system to monitor viral transmission in the presence of neutralizing antibodies (nAb). Separation of producer and target cells ablated nAb resistant transmission, suggesting that cell-cell contact was essential. Furthermore nAb resistant transmission was dependent upon all four co-receptors. These observations confirm HCV immune evasion by cell-to-cell transfer and have major implications for anti-glycoprotein targeted therapies.