No description available.

A great interest has been shown for self-assembled organic nano-structures that can be used in a variety of optoelectronic applications, from element detection to home electronics. It is known from experimental research that sexiphenyl (6P) grown on muscovite mica substrate form uniaxially self-assembled nanofibers which together with sexithiophene (6T) deposited on top gives the possibility to tune their polarized emission. A key to continue develop and explore the full potential of this technique is to understand the mechanisms behind the growth. This thesis investigate the initial growth of 6P and 6T on a 6Pˆ<img src="http://www.diva-portal.org/cgi-bin/mimetex.cgi?%5Cleft(11%20%5Cbar%7B1%7D%20%5Cright)%20%20%20" /> nanofiber substrate through Molecular Dynamics (MD) simulations. The adsorption of the molecules has been simulated with Simulated Annealing (SA) where 6P align perfectly with the substrate for all coverage while 6T starts to align after a certain amount of coverage. Both molecules show a monotonic increase in the adsorption energy per molecule with an increasing coverage. The surface diffusion of the molecules has been studied and shows a higher movement for both in the direction of the longmolecular axis. / Project P25154-N20 "Hetero-epitaxy of organic-organic nanofibers"

Cette thèse a pour but de développer le pendant in silico des étapes clés du Fragment-Based Drug Design (FBDD), et ce dans le cadre plus général du développement de l'outil S4MPLE. Le FBDD génère des ligands drug-like à partir de petites molécules (fragments). Après une étape de validation de S4MPLE et de sa fonction d’énergie, un recentrage autour du FBDD est réalisé, à travers le docking puis l'optimisation virtuelle de fragments par growing ou linking (G/L). Cette stratégie reposesur 1) la création d’une chimiothèque focalisée en connectant un ou deux fragment(s) avec des linkers pré-générés, et 2) l’échantillonnage avec S4MPLE des composés chimères dans le site avec des contraintes. Des simulations de G/L plus ou moins ambitieuses (site flexible, ajout de H2O libres) permettent de valider cette approche avec des études rétrospectives basées sur des données expérimentales. La dernière phase de la thèse a consisté à appliquer ce protocole in silico à un projet de l’entreprise. / This work aims to develop in silico methods targeting the key stages of Fragment-Based Drug Design (FBDD), participating to the development of the molecular modeling tool S4MPLE. Briefly, FBDD generates ıdrug-likeı ligands from small organic molecules called fragments. After a validation step of S4MPLE and its energy function, the work focused on FBDD: molecular docking of fragments and their subsequent virtual optimization. The latter mimics standard evolution strategies in FBDD(growing and linking). This in silico approach involves among other two key stages 1) building of a focused library by plugging in pre-generated linkers into reference fragments using rules and 2) sampling of these new compounds under atomic and binding site constraints. Validation simulations, relying on known experimental data, included ıclassicalı growing / linking and more challenging ones (site flexibility, free waters). Finally, this strategy is applied to one project of the company.

Submitted by MARCIA ROVADOSCHI (marciar@unifra.br) on 2018-08-20T12:55:10Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_MarianaZancanTonel.pdf: 6177598 bytes, checksum: e830fe652c79ad380053f80cae3e2382 (MD5) / Made available in DSpace on 2018-08-20T12:55:10Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_MarianaZancanTonel.pdf: 6177598 bytes, checksum: e830fe652c79ad380053f80cae3e2382 (MD5) Previous issue date: 2017-08-25 / Graphene is a nanomaterial that has several applications including drug delivery and pollutant remover. However, graphene is hydrophobic, which makes it difficult to apply in biological media, and one of the alternatives is through functionalization. At the same time, aromatic molecules are precursors of several essential compounds for life, and are also important in industry. However, some of them are pollutants that can severely affect people and the environment, so developing effective removal methods is extremely interesting. Some molecules of biological interest like dopamine and serotonin have an aromatic part, recent studies show the use of these molecules as mediators for specific and selective drug delivery. Therefore, the study of the interaction of these molecules as pure and modified graphene is of great importance in the biomedical area as well as for diagnostic and treatment studies. In this work, we perform a theoretical study through the density functional theory; initially we analyze the changes caused by the effect of the concentration of the functional groups -COOH, -COH, -OH, -O- or -NH2 on graphene. The results show that in all cases it is possible to modulate the electronic properties depending on the number and location of the groups. Subsequently, we analyzed the graphene pure and functionalized with a group -COOH, -COH, -OH, -O- or -NH2, with the molecules of biological interest as dopamine, serotonin and the pollutants: benzene, aniline, benzoic acid and phenol. The results show that all interactions occur under a physical adsorption regime, there are no changes in the original geometric structures of the molecules after adsorption, it may be of interest to create possible routes as mediators for the delivery of drugs and to assist in the treatment of various diseases or in a system of removal of pollutants based on pristine and modified graphene. Finally, we developed a method to parameterize the benzene-benzene and benzene-graphene force field through the data obtained from the ab initio calculations, the results obtained agree with studies described in the literature. Thus, this work presents the understanding through the simulation of the biomedical part for drug delivery systems, and removal of pollutants, in addition to the parameterization to be used in simulations of the biological environment which may aid in the development of future experimental studies. / O grafeno é um nanomaterial que possui diversas aplicações tecnológicas entre elas como carreador de fármacos e removedor de poluentes. No entanto, o grafeno é hidrofóbico, o que dificulta sua aplicação em meios biológicos, sendo que uma das alternativas para controlar este problema é através de funcionalizações. Paralelamente, moléculas aromáticas são precursoras de diversos compostos imprescindíveis para a vida, e também são importantes na indústria. No entanto, algumas delas são poluentes que podem afetar severamente as pessoas e o meio ambiente. Assim, o desenvolvimento de métodos efetivos para remoção desses é extremante importante. Algumas moléculas de interesse biológico como a dopamina e serotonina apresentam parte aromática. Estudos recentes têm mostrado a utilização dessas moléculas como mediadoras para entrega de fármacos específica e seletiva. Portanto, o estudo dessas moléculas visando este tipo de aplicação é de grande importância na área biomédica. Realizamos um estudo teórico através da Teoria do Funcional da Densidade. Inicialmente, analisamos as alterações causadas pelo efeito da concentração de grupos funcionais -COOH, -COH, -OH, -O- ou -NH2 no grafeno. Os resultados mostram que em todos os casos é possível modular as propriedades eletrônicas dependendo do número e do local dos grupos. Posteriormente, analisamos o grafeno puro e funcionalizado com um grupo –COOH, -COH, -OH, –O- ou -NH2, com as moléculas de interesse biológico dopamina, serotonina e os poluentes benzeno, anilina, ácido benzóico e fenol. Os resultados mostram que todas as interações ocorrem sob um regime de adsorção física, sem alterações nas estruturas geométricas originais das moléculas após adsorção. Esses resultados são de interesse para criar possíveis rotas como mediadores para a entrega de fármacos e auxiliar no tratamento de várias doenças ou ainda em um sistema de remoção de poluentes baseados no grafeno puro e modificado. E, por fim, desenvolvemos um novo método para parametrizar campo de força do benzeno-benzeno e benzeno-grafeno através dos dados obtidos dos cálculos ab initio. Os resultados obtidos concordam com estudos descritos na literatura. Dessa forma, este trabalho apresenta a compreensão através da simulação da parte biomédica para sistemas de drug delivery, e remoção de poluentes, além da parametrização para ser usado em simulações do meio biológico o que poderá auxiliar no desenvolvimento de estudos experimentais futuros.

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No. of bitstreams: 1 brunaluanamarcial.pdf: 8389291 bytes, checksum: 93256796394730c4d8f7a200fe2be582 (MD5) Previous issue date: 2013-07-26 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As Metaloproteinases de Matriz (MMPs) desempenham um papel crucial nos processos fisiológicos e condições patológicas tais como progressão tumoral e metástases. Nos últimos anos, tem sido proposto uma série de inibidores de MMPs (IMMPs), incluindo as Tetraciclinas Quimicamente Modificadas (CMTs), as quais têm apresentado resultados promissores em ensaios com modelos pré-clínicos de câncer. No entanto, até o presente não havia nenhum estudo da estrutura-atividade desses compostos. Neste sentido, na presente tese foram combinadas as metodologias teóricas da Teoria do Funcional da Densidade (DFT), Docking molecular e simulação de Dinâmica Molecular (DM) para elucidar o mecanismo de interação das CMTs com o sítio ativo das MMPs. Primeiramente a estrutura e estabilidade dos modelos moleculares miméticos do sítio ativo da MMP-2 representados por: [Zn(LHn)(H2O)2]2+x (n = 0, 1, 2 e x = -2, -1, 0) e [Zn(L)(His)3], onde L representa CMT1, -3, -4, -7 e -8, foram calculados usando DFT. O efeito do solvente e do pH foram também avaliados. Os resultados sugerem que a coordenação com o zinco ocorra no sítio VI(O11O12), o qual é igualmente favorável para a CMT-3 (log β = 15,9) e CMT-8 (log β = 21,3). Esta análise inicial evidenciou que a atividade das CMTs como inibidoras de MMP estaria diretamente relacionada à sua estrutura. Na segunda fase do trabalho foi investigada a interação das CMTs diretamente com o sítio ativo da MMP-2 (1QIB) combinando os métodos de docking molecular, simulações de DM e cálculos de energia livre. Um novo conjunto de parâmetros para os átomos de Zn(II) estrutural e catalítico da enzima foi calculado, validado e depositado dentro do campo de forças AMBER. As CMTs foram otimizadas no nível B3LYP/6-31G(d) e “docadas” dentro do sítio ativo da MMP-2. As melhores soluções foram minimizadas e submetidas a 12ns de simulação de DM. A energia livre de ligação foi calculada usando as metodologias de integração termodinâmica e MMPBSA. Os principais resultados mostram que as CMTs coordenam-se ao Zn(II) através do sítio VI(O11-O12), como proposto experimentalmente. Com exceção do análogo CMT-3 que está envolvido em contatos hidrofóbicos e interações de van der Waals com aminoácidos do bolso S1’da enzima e ainda interage com o Zn(II) pelo O11. A análise da energia livre de ligação revela uma maior afinidade entre o análogo CMT-3 com o sítio ativo da MMP-2, seguido pela CMT-7 e CMT-8, sendo que a diferença de energia varia apenas de 3 kcal mol1. De acordo com os resultados, é possível inferir que a ocupação do canal S1’ seria um fator fundamental para a resposta biológica da CMT-3, enquanto que as demais CMTs, por impedimento estérico, não entram no túnel hidrofóbico da enzima. Os resultados apresentados nesta tese tratam do primeiro estudo em nível molecular da interação de CMTs com metaloproteínas, como contribuição para a compreensão das observações experimentais, sobretudo dos testes biológicos, e ainda uma referência direta para o desenho de novos análogos das CMTs com maior potencial biológico. / Matrix Metalloproteinases (MMPs) play a critical role in physiological processes and pathological conditions such as tumor progression and metastasis. In recent years, a number of MMP inhibitors (MMPIs) have been proposed, including the chemically modified tetracyclines (CMTs), which have been evaluated in preclinical cancer models showing promising results. However, until present there were no studies on the structure-activity relationship for these compounds. In this sense, the present thesis focuses on the direct interaction of CMTs with the active site of the MMPs. Density Functional Theory (DFT), molecular docking and molecular dynamics (MD) simulations were accomplished for seven CMT derivatives. Firstly the structure and stability of mimetic molecular models of active site of MMP-2 represented by: [Zn(LHn)(H2O)2]2+x (n = 0, 1, 2 and x = -2, -1, 0) and [Zn(L)(His)3], where L=CMT-1, CMT-3, CMT-4, CMT-7 and CMT-8, were calculated at DFT level. The solvent and pH effects were also evaluated. The results suggested that the coordination at the O11-O12 site (site VI) was quite favorable to CMT-3 (log β = 15,9) and CMT-8 (log β = 21,3). This initial analysis showed that the activity of CMTs as inhibitors of MMP is directly related to its structure. In the second stage of the study, we investigated the interaction of CMTs directly with the active site of MMP-2 (1QIB). New sets of parameters were proposed for structural and catalytic zinc atoms in order to study MMPs and their complexes by means of the AMBER force field. The CMTs ligands were optimized at the B3LYP/6-31G(d) and docked onto the active site of MMP-2. The best solutions were minimized and subjected to 12ns MD simulation. The binding free energy was calculated using the methods of thermodynamic integration and MM-PBSA. The main results showed that the CMTs bind to the catalytic zinc of the MMP-2 enzyme through the O11-O12 moiety (site VI) as proposed experimentally. The exception was the CMT-3 analogue which is involved in hydrophobic contacts and van der Waals interactions with amino acids of the S1’ pocket in the MMP-2 enzyme and also interacts with the Zn (II) by O11. The binding energy calculated in solution predicts the CMT-3 complexes as the most favorable, followed by the CMT-7 and CMT-8 analogues, whose energy difference is within 3 kcal mol-1. These results suggest that the occupancy of S1’ pocket is an important molecular feature for biological response of CMT-3, while the other CMTs do not enter the hydrophobic tunnel of the enzyme due to the steric hindrance. The results presented in this thesis are the first step towards understanding the mechanism of CMTs as MMP inhibitors at a molecular level and could be a significant contribution to the understanding of experimental observations, especially the biological tests and the CMTs action mechanism as MMP inhibitors, allowing the design of new analogues with enhanced biological potency.

Dans le cadre de la vitrification de déchets nucléaires, la connaissance et la maîtrise des propriétés structurales et dynamiques des verres incluant les radioéléments sont importantes (dans le liquide et le solide). Elles influencent notamment la qualité du colis de verre, la durée de vie du procédé de vitrification et la quantité de produits de fission qu’il est possible d’introduire. Des simulations de dynamique moléculaire ont été réalisées afin d’analyser l’influence de la composition des matrices vitreuses sur les propriétés structurales et dynamiques. Le verre nucléaire industriel R7T7 étant composé d’un trop grand nombre d’oxydes (une trentaine) pour être simulé correctement, un verre simplifié, composé des oxydes SiO2, B2O3 et Na2O (majoritaires du verre R7T7) a été préféré. L’ajout de La2O3 permet de simuler l’impact des produits de fission et les actinides mineurs sur les propriétés de la matrice vitreuse. Les deux systèmes SiO2-B2O3-Na2O et SiO2-B2O3-Na2O-La2O3 ont permis d’étudier l’effet du sodium et du lanthane sur différentes propriétés. Au cours de ces travaux, un champ de force polarisable a été développé pour réaliser les simulations. Nos calculs à température ambiante ont permis de reproduire les résultats expérimentaux de la structure, de la répartition BIII/B IV, de la densité, avec un bon accord. Une étude a été menée dans le liquide pour l’analyse de la viscosité et de la conductivité électrique. La spéciation B IV/B III et l’influence des changements structuraux sur la densité avec l’augmentation de la température ont également été observées au cours de trempes thermiques. Les limites actuelles de cette approche sont également décrites. / As result of the nuclear waste vitrification, the knowledge and understanding of the dynamic and structural properties of glasses, including the behavior of radionuclides, is important (in liquid and solid phases). It can influence the glass waste properties, the lifetime of the vitrification process and the amount of radionuclides introduced in the glass matrix. Molecular dynamic simulations have been done to study the influence of the glass matrix composition into the structural and dynamic properties of the glass. A simplified glass, with 3 major oxides of the R7T7 glass such as SiO2, B2O3 and Na2O, have been used to simulate the R7T7 industrial nuclear glass (a 30 oxides glass). The inclusion of La2O3 allows us to simulate the impact of fission products and minor actinides into the properties of the glass matrix. Both systems, the SiO2-B2O3-Na2O and SiO2-B2O3-Na2O-La2O3, allow us to study the sodium and lanthanum effect on the properties of the glass. During this work, a polarizable force field has been developed to do these simulations. The results obtained at room temperature let us reproduce the experimental results of the structure, the distribution of BIII/BIV and the density. A study has been done on the viscosity and electrical conductivity of the liquid. The distribution BIV/BIII and the influence of the structural changes on the density along with the temperature have also been observed with thermal quenchings. The current limits of this approach are also described.

Le champ de force CLAYFF est largement employé pour modéliser les interfaces de minéraux argileux – et minéraux apparentés – avec une phase aqueuse. Dans les simulations, les particules d’argile sont typiquement représentées par des feuillets semi-infinis, ainsi seules les surfaces parallèles au plan du feuillet (surfaces basales) sont considérées. Cette simplification est valable dans la mesure où ces surfaces sont majoritaires, mais les feuillets d’argile sont en réalité de taille nanométrique et terminés par des surfaces latérales, ou bordures. Ces surfaces peuvent non seulement adsorber les espèces en solution mais sont aussi sujettes aux transferts de proton, et tous les processus physico-chimiques liés à l’acidité de la phase aqueuse se produisent de façon prédominante au niveau des bordures. En ajoutant au champ de force CLAYFF un terme angulaire métal-O‑H dont les paramètres ont été correctement ajustés, les simulations réalistes des interfaces de bordure deviennent possibles.Les paramètres des termes Al-O‑H et Mg-O‑H ont été obtenus à partir de calculs DFT sur des modèles structuraux du bulk, de la surface basale et de la bordure de la gibbsite Al(OH)3 et de la brucite Mg(OH)2, dont les feuillets peuvent être considérés comme le squelette des minéraux argileux et apparentés. De plus, le terme Si-O‑H a été paramétré à partir d’un modèle de bordure de la kaolinite Al2Si2O5(OH)4. Les propriétés structurales et dynamiques issues de simulations de dynamique moléculaire DFT et classiques basées sur CLAYFF avec et sans terme métal-O‑H ont été comparées. Le champ de force modifié améliore nettement la description des surfaces hydroxylées : l'orientation et la dynamique librationnelle des groupes hydroxyles, les liaisons hydrogène dans lesquelles ils sont impliqués, et la coordination des atomes de métal appartenant aux bordures sont tous plus proches de la réalité. / The CLAYFF force field is widely used to model the interfaces of clay minerals – and related layered materials – with an aqueous phase. In the simulations, clay particles are typically represented by semi-infinite layers, i.e. only surfaces parallel to the layer plane (basal surfaces) are considered. This simplification is acceptable to a certain extent, but clay layers are really nanosized and terminated by lateral surfaces or edges. These surfaces can not only adsorb solvated species but are also subject to proton transfers, and all physico-chemical processes related to the aqueous phase acidity predominantly occur at the edges. By adding to the CLAYFF force field a Metal-O‑H angle bending term whose parameters are correctly adjusted, the simulations of edge interfaces become possible.The parameters of Al-O‑H and Mg-O‑H terms were obtained from DFT calculations on bulk, basal surface and edge structural models of gibbsite Al(OH)3 and brucite Mg(OH)2, whose layers can be considered as the backbones of clay minerals and related materials. In addition, the Si-O‑H term was parametrized from an edge model of kaolinite Al2Si2O5(OH)4 . Molecular dynamics simulations based on DFT and on CLAYFF with and without Metal-O‑H term were performed. The modified force field clearly improves the description of hydroxylated surfaces : the orientation and the librational dynamics of the hydroxyl groups, the hydrogen bonding, and the coordination of metal atoms belonging to the edge are all closer to reality.

In this licentiate thesis the luminescence properties of two flexible conjugated dyes have been studied. The first, Pt1, is a platinum(II) acetylide chromophore used in optical power limiting materials. The second is a set of optical probes known as luminescent conjugated oligothiophenes (LCOs), which are used to detect and characterize the protein structures associated with amyloid diseases such as Alzheimer’s disease. MM3 and CHARMM force field parameters have been derived for the Pt1 chromophore and LCOs, respectively, based on potential energy surface references calculated at the density functional theory (DFT)/B3LYP level of theory. The parameters have been used to perform room temperature molecular dynamics simulations of the chromophores in solvent, where tetrahydrofuran was used for Pt1 and water for the LCOs. Conformationally averaged absorption spectra were obtained, based on response theory calculations at the time-dependent DFT(TDDFT)/CAM-B3LYP level of theory for a selection of structures from the simulations. For one of the LCOs, p-HTAA, force field parameters were also created describing the dominant first excited state, based on TDDFT/B3LYP reference potential energy surfaces. These were used for molecular dynamics simulations of the chromophore in the excited state, allowing the creation of an emission spectrum. A theoretically obtained Stokes shift of 112 nm could be computed based on the absorption and emission spectra, which is in good agreement with the experimental value of 124 nm. In addition, a quantum mechanics/molecular mechanics study of the effects of solvation on the absorption properties of the p-HTAA chromophore in water has been conducted, resulting in two models for including these effects in the averaged spectra. The first includes explicit water molecules in the form of point charges and polarizable dipole moments, and results in an absorption wavelength that is blueshifted by 2 nm from a high quality reference calculation. The second model involves the complete removal of the solvent as well as the ionic groups of the chromophore. The resulting absorption wavelength is blueshifted by an additional 4 nm as compared to the first model, but requires only one fifth of the computational resources.

No description available.

Force fields of 3d objects are used for different purposes in computer graphics as skeletonization and collision detection. In this paper we present a novel method to approximate the force field of a discrete 3d object in linear time. Similar to the distance transformation we define a rule that describe how the forces associated with boundary points are propagated into the interior of the object. The result of this propagation depends on the order in which the points of the object are processed. Therefore we analyze how to obtain an order-invariant approximation formula. For a chosen iteration order (i, j, k) the set of boundary points that influence the force of a particular point p of the object can be described by a spatial region Rijk. The geometries of these regions are characterized both for the Cartesian and the body-centered cubic grid (bcc grid). We show that in the case of the bcc grid these regions can be combined in such a way that E3 is uniformly covered which basically means that each boundary point is contained in the same number of regions. Based on the covering an approximation formula for the force field is proposed that has linear complexity and gives good results for standard objects. We also show that such a uniform covering can not be built from the regions of influence of the Cartesian grid. With our method it becomes possible to use features of the force field for a fast and topology preserving skeletonization. We use a thinning strategy on the bcc grid to compute the skeleton and ensure that critical points of the force field are not removed. This leads to improved skeletons with respect to the properties of centeredness and rotational invariance.