abstract: How water behaves at interfaces is relevant to many scientific and technological applications; however, many subtle phenomena are unknown in aqueous solutions. In this work, interfacial structural transition in hydration shells of a polarizable solute at critical polarizabilities is discovered. The transition is manifested in maximum water response, the reorientation of the water dipoles at the interface, and an increase in the density of dangling OH bonds. This work also addresses the role of polarizability of the active site of proteins in biological catalytic reactions. For proteins, the hydration shell becomes very heterogeneous and involves a relatively large number of water molecules. The molecular dynamics simulations show that the polarizability, along with the atomic charge distribution, needs to be a part of the picture describing how enzymes work. Non Gaussian dynamics in time-resolved linear and nonlinear (correlation) 2D spectra are also analyzed. Additionally, a theoretical formalism is presented to show that when preferential orientations of water dipoles exist at the interface, electrophoretic charges can be produced without free charge carriers, i.e., neutral solutes can move in a constant electric field due to the divergence of polarization at the interface. Furthermore, the concept of interface susceptibility is introduced. It involves the fluctuations of the surface charge density caused by thermal motion and its correlation over the characteristic correlation length with the fluctuations of the solvent charge density. Solvation free energy and interface dielectric constant are formulated accordingly. Unlike previous approaches, the solvation free energy scales quite well in a broad range of ion sizes, namely in the range of 2-14 A° . Interface dielectric constant is defined such that the boundary conditions in the Laplace equation describing a micro- or mesoscopic interface are satisfied. The effective dielectric constant of interfacial water is found to be significantly lower than its bulk value. Molecular dynamics simulation results show that the interface dielectric constant for a TIP3P water model changes from nine to four when the effective solute radius is increased from 5 A° to 18 A° . The small value of the interface dielectric constant of water has potentially dramatic consequences for hydration. / Dissertation/Thesis / Doctoral Dissertation Chemistry 2016

Le but de cette thèse est une revisite du potentiel SIBFA. Ceci inclut un travail et une réflexion sur la méthodologie de cette approche avec une implémentation proposant une utilisation plus large. De plus, une nouvelle calibration de champ de forces raffiné est permise aujourd’hui. En effet, la décomposition d’énergie intermoléculaire SAPT donne accès à toutes les composantes avec rigueur. La reproduction des résultats ab-initio par un potentiel analytique laisse entrevoir des applications prometteuses. Au-delà du coup de calcul considérablement réduit par rapport aux méthodes de chimie quantique, son intégration dans un code de dynamique moléculaire ouvre les portes à de nombreuses études encore plus prometteuses hors de portée de la chimie quantique. Enfin l’optimisation de ce code, avec une parallélisation bien étudiée, en feront un outil majeur de la biochimie. Dans une première partie, nous introduirons les notions et principes essentiels à la dynamique moléculaire. Un premier chapitre exposera la mécanique classique utilisé dans les programmes les plus distribués et utilisés. Un second chapitre introduira les méthodes permettant un meilleur traitement des interactions non-covalentes essentielles dans les études de complexes ligand-récepteur. Une seconde partie abordera de manière plus concrète la stratégie d’implémentation de SIBFA dans Tinker. Celle-ci s’organisera autour de trois chapitres, traitant chaque composante énergétique intermoléculaire. L’objectif de cette thèse est de proposer un socle solide autour du traitement des interactions non covalentes dans le cadre des champs de forces polarisables de dernières générations et de présenter le modèle d’eau hybride AMOEBA/SIBFA. / The purpose of this thesis is to revisit the potential of SIBFA (Sum of Interactions Between Fragments Ab initio computed) [...]

No description available.

Amyloidogenic diseases, such as Alzheimer's disease (AD) and Type II Diabetes (T2D), are characterized by the accumulation of amyloid aggregates. Despite having very different amino-acid sequences, the underlying amyloidogenic proteins form similar supramolecular fibril structures that are highly stable and resistant to physical and chemical denaturation. AD is characterized by two toxic lesions: extracellular amyloid β-peptide (Aβ) plaques and intracellular neurofibrillary tangles composed of microtubule-associated protein tau. Similarly, a feature of T2D is the deposition of islet amyloid polypeptide (IAPP) aggregates in and around the pancreas. The mechanisms by which Aβ, tau, and IAPP aggregate, and cause cell death is unknown; thus, gaining greater insight into the stabilizing forces and initial unfolding events is crucial to our understanding of these amyloidogenic diseases. This work uses molecular dynamics (MD) simulations to study the secondary, tertiary, and quaternary structure of Aβ, tau, and IAPP. Specifically, this work used the Drude polarizable force field (FF), which explicitly represents electronic polarization allowing charge distributions to change in response to perturbations in local electric fields. This model allows us to describe the role charge plays on protein folding and stability and how perturbations to the charge state drive pathology. Studies were conducted to address the following questions: 1) What are the stabilizing forces of fibril and oligomeric structures? 2) How do charge-altering mutations modulate the conformational ensemble and thermodynamic properties of Aβ? 3) How do charge-altering post-translational modifications of Aβ and tau modulate changes in the conformational ensembles? These studies establish that shifts in local microenvironments play a role in fibril and oligomer stability. Furthermore, these studies found that changes in protein sequence and charge are sufficient to disrupt and change the secondary and tertiary structure of these amyloidogenic proteins. Overall, this dissertation describes how charge modulates protein unfolding and characterizes the mechanism of those changes. In the long term, this work will help in the development of therapeutics that can target these changes to prevent protein aggregation that leads to cell death. / Doctor of Philosophy / Protein aggregation is the hallmark of many chronic diseases, such as Alzheimer's disease (AD) and Type II Diabetes (T2D). The formation of two toxic aggregates: amyloid β-peptide (Aβ) plaques and neurofibrillary tangles composed of microtubule-associated protein tau are some of the key characteristics of AD. In addition, the formation of islet amyloid polypeptide (IAPP) aggregates in the pancreas is thought to play a role in the development of T2D. The pathways by which the proteins Aβ, tau, and IAPP aggregate are unknown; thus, gaining a greater insight into the properties that may cause these diseases is necessary to develop treatments. By studying these proteins at the atomistic level, we can understand how small changes to these proteins alter how they misfold in a way that promotes toxicity. Herein, we used a computational technique called molecular dynamics (MD) simulations to gain new insights into how protein structure changes. We explored the dynamics of these proteins and investigated the role that charge plays in protein folding and described how charge modulates protein folding and characterized the mechanism of those changes. This work serves as a characterization of protein folding and sets the ground for future structural studies and drug development.

Simulação de Dinâmica Molecular (MD) foi utilizada para se explorar propriedades estruturais e dinâmicas de eletrólitos poliméricos, poli(oxietileno), PEO, PEO-LiClO4 em três concentrações de sal e em duas temperaturas (373 e 500 K), visando contribuir para o entendimento do mecanismo pelo qual os íons são transportados na matriz polimérica. Nas simulações MD foi utilizado um modelo de átomos unidos para o PEO. O modelo do PEO (32 cadeias de PEO com peso molecular de 1175) foi validado pela comparação do fator de estrutura estático, S(k), calculado com o obtido por espectroscopia de espalhamento de nêutrons para o PEO puro. Um pico em vetor de onda pequeno foi observado no S(k) quando LiClO4 foi adicionado na matriz do PEO, indicando a presença de ordem estendida no PEO-LiClO4 fundido. Pares iônicos de contato foram observados, os quais são favorecidos quando a temperatura aumenta. As cadeias do PEO se tomam menos estendidas (menor raio de giração, Rg) com a adição de sal. O raio de giração aumenta com o aumento da temperatura em concentração baixa de sal e é fracamente afetado pela temperatura em concentração alta de sal. A dinâmica dos cátions é afetada pelo seu ambiente local, sendo mais favorecida na direção dos átomos de oxigênio do PEO. Os cátions apresentam movimentos difusivo e em saltos. A relaxação das cadeias do PEO, assim como a difusão dos íons, é maior nos sistemas de menor concentração de LiClO4 e em temperatura elevada. / In this work, Molecular Dynarnics (MD) simulation has been performed to evaluate structural and dynamics properties of the polymer electrolyte poly(oxietilene) PEO-LiClO4 for three salt concentration and two temperatures (373 and 500 K), in order to understand the ionic transport mechanism in the polymeric matrix. A united atoms model has been used for PEO. The PEO model has been validated by comparing calculated static structure factor S(k) of pure PEO at 363 K (32 PEO chains with a molecular weight of 1175) with previous experimental data obtained by neutron scattering spectroscopy. A low wave-vector peak indicates an extended-range order in PEO-LiClO4 melts. Contact ionic pair are observed, which are favoured as temperature increases. PEO chains as a whole becomes less extented (smaller radius of gyration) uppon addition of LiClO4. Radius of gyration increases with temperature at low salt concentration, but it is only marginally affected by temperature at high concentration. Cations dynamics is affected by the local neighborhood, being faster in the direction of PEO oxygen atoms. Cations motion display diffusion and hopping events. Relaxation time of PEO chains, as well as ionic diffusion, increase with temperature and decrease with LiClO4 concentration.

Neste trabalho, conjuga-se teoria, experimento e simulação para o estudo de líquidos iônicos. As componentes observadas na região de freqüências baixas (compreendida entre 0 a 200 cm-1) nos espectros vibracionais são resultado da dinâmica roto-translacional e das interações intermoleculares. Dessa forma, as espectroscopias vibracionais são inseridas no contexto das técnicas adequadas para o estudo da dinâmica de líquidos. Na parte experimental deste trabalho, é discutida a dependência com a temperatura dos espectros Raman em freqüências baixas, como uma maneira para investigar os efeitos da vitrificação sobre a dinâmica dos líquidos iônicos. A simulação computacional pelo método da dinâmica molecular é utilizada de forma conjugada a modelos polarizáveis para descrever a evolução temporal da polarizabilidade, com o objetivo de simular os espectros Raman. A partir da comparação sistemática entre resultados obtidos de modelos distintos e da complementaridade das informações obtidas desses modelos, mostra-se um cenário geral para o estudo da relaxação da polarizabilidade em líquidos iônicos. O método da equalização da eletronegatividade (EEM) foi utilizado e um conjunto de parâmetros para os cátions do tipo 1-n-alquil-3- metil imidazólio é proposto para o cálculo da dinâmica das cargas atômicas parciais e da polarizabilidade no líquido resultante da interação das espécies polarizáveis com as vizinhas. / In this work, theory, experiment and simulation are conjugated to investigate ionic liquids. The observed components in the low frequency part of the spectra (the region between 0 e 200 cm-1) results from the roto-translational dynamics and from inter molecular interactions. In this sense, the vibrational spectroscopies are inserted in the context of techniques suitable for the studies of liquid dynamics. At the experimental part of this work, the temperature dependence of the low frequency part of the Raman spectra of ionic liquids is discussed with the purpose of comprehend the main changes across the glass transition phenomena. Computer simulation of molecular dynamics is used with appropriated polarizable models to describe the time evolution of the polarizability, with the aim to simulate the Raman spectra. From the systematic comparison of the results obtained from distinct models and from the complementarities of the information derived form each theoretical model we scrutinize one general landscape for the study of polarizability relaxation in such complex ionic systems. The electronegativity equalization method (EEM) was used and parameter set for the cations 1-n-alkyl-3-methylimidazolium is proposed for the calculation of the dynamics of the atomic partial charges and the polarizability considering the interactions of the polarizable ions with its environment in the liquid

Neste trabalho, conjuga-se teoria, experimento e simulação para o estudo de líquidos iônicos. As componentes observadas na região de freqüências baixas (compreendida entre 0 a 200 cm-1) nos espectros vibracionais são resultado da dinâmica roto-translacional e das interações intermoleculares. Dessa forma, as espectroscopias vibracionais são inseridas no contexto das técnicas adequadas para o estudo da dinâmica de líquidos. Na parte experimental deste trabalho, é discutida a dependência com a temperatura dos espectros Raman em freqüências baixas, como uma maneira para investigar os efeitos da vitrificação sobre a dinâmica dos líquidos iônicos. A simulação computacional pelo método da dinâmica molecular é utilizada de forma conjugada a modelos polarizáveis para descrever a evolução temporal da polarizabilidade, com o objetivo de simular os espectros Raman. A partir da comparação sistemática entre resultados obtidos de modelos distintos e da complementaridade das informações obtidas desses modelos, mostra-se um cenário geral para o estudo da relaxação da polarizabilidade em líquidos iônicos. O método da equalização da eletronegatividade (EEM) foi utilizado e um conjunto de parâmetros para os cátions do tipo 1-n-alquil-3- metil imidazólio é proposto para o cálculo da dinâmica das cargas atômicas parciais e da polarizabilidade no líquido resultante da interação das espécies polarizáveis com as vizinhas. / In this work, theory, experiment and simulation are conjugated to investigate ionic liquids. The observed components in the low frequency part of the spectra (the region between 0 e 200 cm-1) results from the roto-translational dynamics and from inter molecular interactions. In this sense, the vibrational spectroscopies are inserted in the context of techniques suitable for the studies of liquid dynamics. At the experimental part of this work, the temperature dependence of the low frequency part of the Raman spectra of ionic liquids is discussed with the purpose of comprehend the main changes across the glass transition phenomena. Computer simulation of molecular dynamics is used with appropriated polarizable models to describe the time evolution of the polarizability, with the aim to simulate the Raman spectra. From the systematic comparison of the results obtained from distinct models and from the complementarities of the information derived form each theoretical model we scrutinize one general landscape for the study of polarizability relaxation in such complex ionic systems. The electronegativity equalization method (EEM) was used and parameter set for the cations 1-n-alkyl-3-methylimidazolium is proposed for the calculation of the dynamics of the atomic partial charges and the polarizability considering the interactions of the polarizable ions with its environment in the liquid

Simulação de Dinâmica Molecular (MD) foi utilizada para se explorar propriedades estruturais e dinâmicas de eletrólitos poliméricos, poli(oxietileno), PEO, PEO-LiClO4 em três concentrações de sal e em duas temperaturas (373 e 500 K), visando contribuir para o entendimento do mecanismo pelo qual os íons são transportados na matriz polimérica. Nas simulações MD foi utilizado um modelo de átomos unidos para o PEO. O modelo do PEO (32 cadeias de PEO com peso molecular de 1175) foi validado pela comparação do fator de estrutura estático, S(k), calculado com o obtido por espectroscopia de espalhamento de nêutrons para o PEO puro. Um pico em vetor de onda pequeno foi observado no S(k) quando LiClO4 foi adicionado na matriz do PEO, indicando a presença de ordem estendida no PEO-LiClO4 fundido. Pares iônicos de contato foram observados, os quais são favorecidos quando a temperatura aumenta. As cadeias do PEO se tomam menos estendidas (menor raio de giração, Rg) com a adição de sal. O raio de giração aumenta com o aumento da temperatura em concentração baixa de sal e é fracamente afetado pela temperatura em concentração alta de sal. A dinâmica dos cátions é afetada pelo seu ambiente local, sendo mais favorecida na direção dos átomos de oxigênio do PEO. Os cátions apresentam movimentos difusivo e em saltos. A relaxação das cadeias do PEO, assim como a difusão dos íons, é maior nos sistemas de menor concentração de LiClO4 e em temperatura elevada. / In this work, Molecular Dynarnics (MD) simulation has been performed to evaluate structural and dynamics properties of the polymer electrolyte poly(oxietilene) PEO-LiClO4 for three salt concentration and two temperatures (373 and 500 K), in order to understand the ionic transport mechanism in the polymeric matrix. A united atoms model has been used for PEO. The PEO model has been validated by comparing calculated static structure factor S(k) of pure PEO at 363 K (32 PEO chains with a molecular weight of 1175) with previous experimental data obtained by neutron scattering spectroscopy. A low wave-vector peak indicates an extended-range order in PEO-LiClO4 melts. Contact ionic pair are observed, which are favoured as temperature increases. PEO chains as a whole becomes less extented (smaller radius of gyration) uppon addition of LiClO4. Radius of gyration increases with temperature at low salt concentration, but it is only marginally affected by temperature at high concentration. Cations dynamics is affected by the local neighborhood, being faster in the direction of PEO oxygen atoms. Cations motion display diffusion and hopping events. Relaxation time of PEO chains, as well as ionic diffusion, increase with temperature and decrease with LiClO4 concentration.

Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2017-07-12T18:05:35Z No. of bitstreams: 1 2016 - Felipe Augusto da Silva.pdf: 12688361 bytes, checksum: 9f1ec0867eb071ebf8dbb7f89606cf25 (MD5) / Made available in DSpace on 2017-07-12T18:05:35Z (GMT). No. of bitstreams: 1 2016 - Felipe Augusto da Silva.pdf: 12688361 bytes, checksum: 9f1ec0867eb071ebf8dbb7f89606cf25 (MD5) Previous issue date: 2016-09-29 / To understand the behavior of molecules in liquid fase is fundamental for comprihend many chemical and physical process, became reference to severa! areas of scientific and tecnologic knowledge. Methods using polarizable continuum model (PCM) have been proposed and revised to achieve more acurated results and the aplicability of the method. MultiPatch is a analitic and eficient molecular smface tesselation method. This smface is necessary to calcule the eletrostatic component of the interaction energy between solute and solvent Delta G s. The method was tested by comparing the results for the smface area and the energy Delta G s obtained using internai methods of the software GAMESS. / Entender o comportamento de mol?culas em fase l?quida ? fundamental para o compreender diversos processos qu?micos e f?sicos, sendo assim refer?ncia para diversas ?reas do conhecimento cient?fico e tecnol?gico. M?todos usando o modelo de cont?nuo polariz?vel (PCM) tem sido propostos e revisados com o objetivo de melhorar a acur?cia dos resultados e a aplicabilidade desse modelo. MultiPatch ? um m?todo anal?tico e eficiente para se obter uma tessela??o da superf?cie molecular necess?ria para o computo de uma das componentes, de origem eletrost?tica, da energia de intera??o entre soluto e solvente Delta G s:. O m?todo foi testado comparando seus resultados para ?rea da superf?cie e a energia Delta G s com o m?todos internos do software GAMESS.

Cette thèse porte sur deux projets visant au développement de nouvelles approches pour simuler les dynamiques moléculaire et électronique avec application à des biomolécules étendues. Dans la première partie nous cherchons à améliorer significativement la précision des simulations des propriétés rédox des protéines. Dans ce contexte, l'objectif est de recourir à de champ de force reposant sur une description multipolaire des interactions électrostatiques (AMOEBA) pour estimer les potentiels redox d'hémoprotéines. Nous avons dérivé des paramètres pour AMOEBA afin de décrire précisément les interactions électrostatiques avec l'hème. Une amélioration très encourageante est obtenue par rapport aux champs de forces standard. Le second projet vise à développer de nouvelles méthodes pour étudier la dynamique des électrons dans des biomolécules à l'échelle attoseconde en incluant les effets d'environnement. Nous avons conçu un couplage original entre la théorie de la fonctionnelle de la densité dépendant du temps (RT-TDDFT) et un modèle de mécanique moléculaire polarisable (MMpol). Une implémentation efficace et robuste de cette méthode a été réalisée dans le logiciel deMon2k. L'utilisation de techniques d'ajustements de densités électroniques auxiliaires permet de réduire drastiquement le coût de calcul des propagations RT-TDDFT/MMpol. La méthode est appliquée à l'analyse de la dissipation d'énergie dans l'environnement d'un peptide excité par un impulsion laser. / This thesis involves two projects devoted to the development of advanced approaches for simulating molecular and electron dynamics in extended biomolecules. The first project aims at significantly improving the accuracy of redox potentials of proteins by numerical simulations. A sophisticated force field relying on a multipolar description of electrostartic interactions (AMOEBA) is used to perform molecular dynamics simulations onheme proteins. We derived parameters for AMOEBA to accurately describe electrostatic interactions with hemein both ferrous and ferric states. Very encouraging improvements are obtained compared to the standard force fields. The second project aims at developing original approaches for simulating ultrafast electron dynamics in biomolecules in contact to polarizable environments. We devised acombination of Real-time Time-Dependent Density Functional Theory (RT-TDDFT) and polarizable Molecular Mechanics (MMpol). An efficient and robust implementation of this method has been realized in deMon2k software. Density fitting techniques allow to reduce the computational cost of RT-TDDFT/MMpol propagations. The methodology is applied to understand the mechanisms of energy dissipation of a peptide excited by a laser pulse.