Desenvolvemos dois modelos estatísticos para água, nos quais diferentes aspectos de sua estrutura são considerados. O modelo geométrico permite diferentes números de coordenação. Em uma aproximação de campo médio mostramos que sob pressão o modelo apresenta linha de coexistência entre fases de baixa e alta densidade, e ponto crítico. A entropia das ligações de hidrogênio tem papel fundamental na definição da inclinação da linha de coexistência. O comportamento do modelo pode estar realcionado como segundo ponto crítico da água super resfriada e com transições líquido-líquido em geral.O modelo da água quadrada é uma versão térmica do modelo do gelo, no qual considera-se a direcionalidade das ligações de hidrogênio. O modelo foi estudado na rede de Bethe e através de simulações de Monte Carlo em três situações diferentes: para a água pura e na presença de solutos polares e apolares. A água quadrada pura não apresenta transição de fase. No modelo para solvente com solutos apolares, medidas de frequência relativa de ligações e do tempo de correlação mostram que o modelo apresenta estruturação da camada de hidratação. Medidas de correlação temporal no modelo de Ising mostram comportamento oposto. Em um estudo preliminar para uma solução com solutos que realizam ligações de hidrogênio não conseguimos encontrar diagramas de coexistência com círculo fechado, para o conjunto de parâmetros utilizados, possivelmente devido à ausência de buracos. / We have developed two statistical models for water in which different features of water structure are considered. In the geometrical model different coordination numbers are present and the model allows for translational disorder. A mean-field treatment shows that under pressure the model exhibits phases of different densities and a coexistence line ending in a critical point. Entropy of the hydrogen network plays an essential role in defining the slope of the coexistence line. The model behavior might be related with the second critical point in supercooled water and to liquid-liquid transitions in general. The square water model is a thermal version of the ice model, and takes into account the directionality of the hydrogen bonds. The model was studied on a Bethe lattice and through Monte Carlo simulations, for three different situations: as pure water and in the presence of polar and apolar solutes. Pure square water does not present a phase transition. In the presence of apolar solutes, first shell square water presents ordering, as shown from comparison of relative frequency of bonds, as well as from study of time correlations. The latter was shown to present opposite behavior in case of an Ising system. In a preliminary study for a solution of hydrogen bonding solutes we were unable to find a closed loop for the sets of parameters chosen. Vacancies might need to be included.

L’objectif de cette étude est d’étudier le rôle de la salive dans la libération des molécules odorantes, par deux approches, in vitro et in vivo. L’effet des protéines salivaires sur la libération de 10 molécules odorantes (5 esters et 5 cétones, de longueur de chaîne hydrophobe variable) a été étudié in vitro dans des systèmes modèles composés de salives artificielles et humaine. Les salives artificielles contiennent les protéines majoritairement présentes dans la salive (mucine et alpha-amylase), seules et en mélange. Les quantités de chaque molécule odorante présentes dans la phase gazeuse à l’équilibre thermodynamique ont été mesurées par une analyse headspace en mode statique couplée à la chromatographie en phase gazeuse (SH-GC). Les coefficients de partage entre l’air et chacun des systèmes modèles ont été calculés pour chacune des molécules. Cette approche in vitro nous a permis de démontrer une diminution des coefficients de partage air/salive artificielle en présence de mucine et d’alpha-amylase, par un effet hydrophobe. Aucun effet cumulatif n’est observé lorsque les deux protéines sont mises ensemble en solution. En présence de salive humaine, une diminution des coefficients de partage est également observée, les esters étant plus affectés par la présence de salive humaine que les cétones. Cette observation est due à une activité des estérases de la salive, qui augmente avec l’hydrophobicité des esters. La libération in vivo du propanoate d’éthyle et de l’hexanoate d’éthyle a été suivie sur 10 sujets par spectrométrie de masse à ionisation chimique à pression atmosphérique (APCI-MS) dans des conditions physiologiques différentes : au repos, après stimulation et après élimination du film salivaire résiduel. La salive de chaque sujet a été caractérisée dans les différentes conditions physiologiques testées. De grandes variations de flux, viscosité et de composition salivaire ont été mises en évidence entre les sujets, ainsi qu’entre les conditions physiologiques pour un même sujet. Les différences observées sur les paramètres de libération in vivo des molécules odorantes sont discutées en regard de ces paramètres physiologiques. Nous avons ainsi observé qu’une viscosité salivaire élevée diminue la quantité de molécules odorantes libérées sur un temps donné. Dans le même temps, la présence d’une quantité importante d’alpha amylase dans la salive augmente de façon significative le temps de libération de la molécule la plus hydrophobe, l’hexanoate d’éthyle. Nous avons ainsi mis en évidence que la rétention des molécules hydrophobes par les protéines salivaires peut induire une modification de leur cinétique de libération en conditions réelles de consommation et pourrait intervenir dans la persistance aromatique. / The aim of this work is to give a deeper understanding of the impact of the salivary composition on aroma release, by two approaches, an in vitro and an in vivo approach. The impact of salivary proteins on the release of 10 aroma compounds (5 esters and 5 ketones, varying in their hydrophobic chain length) was first investigated by in vitro model systems composed of artificial and human saliva. Artificial salivas were composed of the main salivary proteins, mucins and alpha amylase, alone and in mixture.The amount of aroma released in the vapor phase at equilibrium was analyzed by Static Headspace Gas Chromatography analysis. Air/system partition coefficients have been calculated. This in vitro approach allowed us to demonstrate the ability of both mucin and alpha-amylase to decrease the release of aroma compounds by hydrophobic effect (increase of retention with aroma hydrophobicity). Interestingly, no cumulative effect was observed when both proteins were mixed together in solution. The release of ketones in presence of human saliva is lower than in water and slightly higher than in the presence of artificial saliva. Esters are more affected by the presence of human saliva than ketones. This observation is due to an esterase activity of saliva, which increases with the hydrophobicity of esters. The in vivo release of ethyl propanoate and ethyl hexanoate was followed on ten subjects by Atmospheric Pressure Chemical Ionization mass spectrometry (APCI-MS) under different physiological conditions: at rest, after stimulation and after removing the superficial salivary coat. The saliva was characterized for each subject and each physiological condition. Great variations were observed between the subjects on the salivary flow, viscosity, composition and for each subject between the physiological conditions. The differences observed on in vivo release parameters are discussed as a function of physiological parameters. We observed that subjects with a more viscous saliva present a lower amount of aroma released. The presence of higher amounts of alpha-amylase increased the time needed to release the more hydrophobic compound, ethyl hexanoate. Our results suggest that the retention of hydrophobic aroma compounds by salivary proteins induces a modification of the kinetics of aroma release in real consumption conditions, and could be responsible for aroma persistence.

No description available.

This thesis entitled “Organic Transformations in Water: Synthetic and Mechanistic Studies towards Green Methodologies” is in two parts. Part-I describes various synthetic studies aimed at developing improved methodologies; Part-II describes certain mechanistic studies directed towards an improved understanding of phase transfer catalysis and the hydrophobic effect. Water is uniquely advantageous as a solvent. It is environmentally benign, non-flammable, liquid over a wide temperature range and possesses a high heat capacity that makes it inherently safe. Water also catalyses chemical transformations between insoluble organic reactants. Water thus serves as a reaction medium, a product partitioner and a reaction catalyst.1 Part-I:- Reactions in Water under both Microwave and Ambient Conditions Part-I is further divided into three chapters. Chapter II deals with reactions of 2-nitroalcohols (2NAs), and is divided into three sections. Section A describes the synthesis of nitroalkanes via the microwave-assisted, water-mediated chemoselective reduction of 2NAs using tributyltin hydride (Bu Scheme 1 ). The 2NAs, synthesized from nitromethane and aldehydes (aliphatic, alicyclic, heterocyclic or m- & p-substituted aromatic aldehydes), were converted into corresponding nitroalkanes in excellent yields. The 2NAs derived either from substituted nitromethane [nitroethane, (nitromethyl)benzene, etc.] or bulky aldehydes (o-substituted aromatic aldehydes), however, failed to furnish nitroalkanes under these conditions. Also a major solvent effect was observed: the extent of conversion was greater in water than in water-polar 3SnH) as reducing agent. The chemoselective reduction of 2NAs to nitroalkanes was observed accidentally while trying to remove the nitro group of 2NAs in a Bu3SnH-AIBN-water system under microwave conditions. When equimolar quantities of 2NA and Bu3SnH were added to water, microwave irradiation led to nitroalkanes (protic solvent mixtures and the reaction did not occur either in aprotic polar or non-polar solvents. Scheme 1. Microwave assisted chemoselective reduction of 2NAs to nitroalkanes in Bu3SnH-water In Section B, the microwave assisted synthesis of nitroalkanes from nitroalkenes has been described. Equimolar quantities of nitroalkene and Bu Scheme 2 ). The nitroalkenes substituted even by bulky groups at C-1 & C-2 were converted into corresponding nitroalkanes. Hence the drawback of the method described in Section A was overcome by employing nitroalkenes as starting materials. 3SnH in water under microwave irradiation, led to excellent yields of corresponding nitroalkanes (Scheme 2). The nitroalkenes substituted even by bulky groups at C-1 & C-2 were converted into corresponding nitroalkanes. Hence the drawback of the method described in Section A was overcome by employing nitroalkenes as starting materials. Scheme 2. Microwave assisted reduction of nitroalkenes to nitroalkanes in Bu3SnH-water In Section C, the synthesis of nitroalkenes via dehydration of 2NAs in a K Scheme 3 ). Thus, the dehydration of 2NAs has been accomplished under relatively mild conditions. (It was observed that the 2NAs bearing bulky groups underwent the retro-Henry reaction rather than dehydration.) 2CO3-water system has been described. This conversion was accomplished at 0-5 °C in 5-30 minutes, the nitroalkenes being isolated in good yields (Scheme 3). Thus, the dehydration of 2NAs has been accomplished under relatively mild conditions. (It was observed that the 2NAs bearing bulky groups underwent the retro-Henry reaction rather than dehydration.) Scheme 3. Dehydration of 2-NAs in aqueous K2CO3 solution Chapter III describes the chemoselective reduction of ketoaldehydes. This was serendipitously discovered during attempted enantioselective reduction of prochiral ketones using amino acid-NaBH Scheme 4 ). The method provides a mild and efficient route for the chemoselective reduction of aldehydes under aqueous basic conditions. 4-Na2CO3 in water. When equimolar quantities of aldehyde and ketone were added to a solution NaBH4 in aqueous Na2CO3 at ambient temperature, the aldehydes were selectively reduced. Good yields of primary alcohols were generally observed with excellent chemoselectivities. Extension of this study to the selective reduction of ketoaldehydes under the above reaction conditions furnished ketoalcohols in > 70% yields with > 80% chemoselectivities (Scheme 4). The method provides a mild and efficient route for the chemoselective reduction of aldehydes under aqueous basic conditions. Scheme 4. Chemoselective reduction of ketoaldehydes with NaBH4-Na2CO3 in water Chapter IV deals with deprotection of various acetals, thioacetals and tetrahydropyranyl (THP) ethers in hexane under ambient conditions, by employing chloral hydrate as reagent. Chloral hydrate is a crystalline solid with pK2 When a a 9.66.stirred suspension of excess chloral hydrate in hexane was treated with the acetal, thioacetal or THP ether, the corresponding aldehyde, ketone and alcohol were obtained in good to excellent yields (stirred suspension of excess chloral hydrate in hexane was treated with the acetal, thioacetal or THP ether, the corresponding aldehyde, ketone and alcohol were obtained in good to excellent yields (stirred suspension of excess chloral hydrate in hexane was treated with the acetal, thioacetal or THP ether, the corresponding aldehyde, ketone and alcohol were obtained in good to excellent yields ( Scheme 5. Chloral hydrate catalyzed hydrolysis of acetals, thioacetals including THP ethers Part-II:- Mechanistic Studies on Phase Transfer Catalysis and The Hydrophobic Effect Part-II is in two chapters. Chapter V describes a study of the mechanism of the phase transfer catalyzed (PTC) nucleophilic reaction of cyanide ion with alkyl halides in decane ( Scheme 7 ). In the extraction mechanism proposed earlier,3 the PTC forms the mixed species, tributylhexadecylphosphonium cyanide (THPB), which is believed to be more soluble in decane than is the starting cyanide. A problem with this explanation is that the positive free energy of transfer of the cyanide ion from the aqueous to the organic phase, which is unlikely to be offset by solvation energy of the hexadecyl and butyl groups. Scheme 6. Cyanide displacement reaction of 1-chloro octane3 The present studies explore the possibility that the reaction occurs via the formation of aggregates resembling reverse micelles ( Figure 1 ). In these, the hydrocarbon residues point outwards, with the ionic species ensconced in a deeply embedded interior along with a certain number of water molecules. Thus, the ionic species are not only shielded from the organic medium, but also stabilized in a relatively polar micro-environment (largely via dipolar interactions and hydrogen bonding). It is assumed that this stabilization energy surpasses the positive free energy of transfer of cyanide ion from aqueous to the organic phase. Figure 1. Typical representation of cyanide displacement reaction in THPB-decane-water micellar pool In fact, NMR studies on the structural dynamics of THPB in solution offered evidence of aggregation. Also, a correlation between the structures of catalyst and reactant was observed in studies with various other PTC’s. Chapter VI deals with the mechanism of the Diels-Alder reaction (DAR) in water. The concept of the hydrophobic effect (HE)4 and preferential hydrogen bonding of water with the polarized transition state5 have been invoked to explain the apparent acceleration of Diels-Alder reactions in water. The present studies explore the possibility that the highly polar water microenvironment stabilizes the transition state. Semi-quantitative rate studies of DAR involving water soluble reactants indicate that the possible role of solvation and hydrogen bonding on the polarized transition state as the key factor in the rate enhancement of water mediated DAR. The DAR in the presence of a catalytic amount of water along with the organic solvent catalyzed the reaction more efficiently, as compared to the reaction in pure organic solvent. It was also observed that there was a prominent effect of traces of water on the rate in solvent-free conditions. .

No description available.

[pt] As doenças trasmitidas pelo sangue, assim como a necessidade de bancos de sangue para um pronto auxílio em casos de acidentes tem estimulado esforços para desenvolver substitutos do sangue. A albumina serica humana (HSA do ingles Human Serum Albumin) é a proteína mais abundante no plasma sanguíneo. A molécula heme é a transportadora de oxigênio no sangue. Portanto, um estudo detalhado da interação HSA/heme seria útil em pesquisas que visam tornar o complexo HSA-heme em um substituto do sangue. Nesta tese, foram usadas técnicas de dinâmica molecular e ferramentas estatísticas para estudar o sistema HSA-heme em solvente explícito. Tanto o ligante quanto a proteína foram também estudados separadamente em meio aquoso. Dentre outros resultados, nosso estudo revelou a organização da água circundante, os efeitos da ligação do heme na HSA, os mecanismos moleculares da ligação do heme, os movimentos coletivos da proteína livre e ligada, assim como também os aminoácidos que atuam como dobradiças moleculares na mudança conformacional que sofre a proteína ao ligar o heme. / [en] Diseases transmitted through the blood, as well as the need for blood banks to help in case of accidents, stimulated efforts to develop blood substitutes. The human serum albumin (HSA) is the most abundant protein in blood plasma. The heme molecule is the carrier of oxygen in the blood. Therefore, a detailed study of the interaction HSA/heme could give useful insights in the research aimed to convert the HSA-heme complex into a blood substitute. In this thesis, molecular dynamics techniques and statistical tools were applied to study the HSA-heme system in explicit solvent. Both ligand and protein were also studied separately in aqueous medium. Among other results, our study reveals the organization of the surrounding water, the effects of the heme upon its binding to HSA, the molecular mechanisms for heme binding, the collective motions of the protein with and without the heme, as well as the amino acids that act as molecular hinges in the conformational change between the free and bound forms of the protein.

Die vorliegende Arbeit beschäftigt sich mit der Untersuchung und Beschreibung der Eigenschaften der synthetischen Dekapeptide Cetrorelix und Ozarelix durch analytische Methoden und computergestützte Modellierung. Diese Moleküle sind hydrophobe, aggregierende Antagonisten des Gonadotropin-Releasing-Hormons (GnRH). Zusätzlich wurden amyloidbildende Peptidstrukturen als Modelle für die Assoziationsprozesse in hydrophoben Peptiden untersucht und visualisiert. Die intrinsische Fluoreszenz der GnRH-Antagonisten und zusätzlich der Peptide Teverelix und D-Phe6-GnRH sowie von verkürzten Fragmenten des Cetrorelix wurde untersucht. Ein Strukturmodell für die Beschreibung der Aggregation der Dekapeptide wurde erarbeitet. Der Aufbau eines Rechenclusters durch das Einbinden der Computer am Lehrstuhl in ein Linux-System zur Verteilung von Rechenprozessen über das Netzwerk ermöglichte die Bereitstellung der notwendigen Leistung zur Realisierung der Berechnungen. Es wurden Werkzeuge zur Modellierung der solvatisierten Aggregate von Peptiden ohne eindeutige Vorzugsstruktur programmiert und in ein Docking-System für beliebige Moleküle eingebunden. Verwendet wurde das Kraftfeld MMFF94 mit einer Erweiterung durch ein Verfahren zur dynamischen Berechnung von Partialladungen in Molekülstrukturen. Solvatisierte Aggregate der Dekapeptide und von bekannten amyloidbildenden Strukturen wurden modelliert (Docking). Berechnet wurden als aggregierend beschriebene Sequenzen und entsprechende Vergleichsstrukturen des Calcitonins, des Insel-Amyloid-Polypeptides, des beta2-Mikroglobulins, des Amyloid-beta-Proteins, des Lactoferrins und weitere Modellpeptide. Die wesentlichen Wechselwirkungen während der Aggregation konnten schließlich anhand von Dynamik-Simulationen der faltblattartigen Dimere des Cetrorelix und Ozarelix beschrieben werden. So wurden die Prozesse der hydrophoben Assoziation und Stabilisierung durch Wasserstoffbrücken von Peptiden veranschaulicht und auf molekularer Ebene erfolgreich analysiert. Die Visualisierung der erhaltenen Modellierungsergebnisse erfolgt durch die Darstellung der Strukturen und Dynamik-Simulationen als interaktive 3D-Modelle in einem für diese Arbeit aufgebauten Internetauftritt. / This work discusses the analysis of the aggregation properties of the gonadotropin releasing hormone antagonists Cetrorelix, Teverelix, Ozarelix and of small amyloid forming model peptides by analytical fluorescence spectroscopy and molecular modelling. A high performance linux compute cluster was developed for calculation of molecular structures. Solvated aggregate clusters of peptides without defined secondary structure were modelled by molecular mechanics methods (forcefield mmff94) in combination with an advanced charge equilibration and docking technique. Molecular dynamics of solvated peptide dimers were implemented and the role of hydrophic association and hydrogen bond formation in hydrophobic peptide aggregates was explained. Finally, an aggregation model for the directed association of hydrophobic peptides is presented. The modelling results, 3d structures and dynamic simulations are visualized in an interactive web material.

Die vorliegende Arbeit beschäftigt sich mit der Untersuchung und Beschreibung der Eigenschaften der synthetischen Dekapeptide Cetrorelix und Ozarelix durch analytische Methoden und computergestützte Modellierung. Diese Moleküle sind hydrophobe, aggregierende Antagonisten des Gonadotropin-Releasing-Hormons (GnRH). Zusätzlich wurden amyloidbildende Peptidstrukturen als Modelle für die Assoziationsprozesse in hydrophoben Peptiden untersucht und visualisiert. Die intrinsische Fluoreszenz der GnRH-Antagonisten und zusätzlich der Peptide Teverelix und D-Phe6-GnRH sowie von verkürzten Fragmenten des Cetrorelix wurde untersucht. Ein Strukturmodell für die Beschreibung der Aggregation der Dekapeptide wurde erarbeitet. Der Aufbau eines Rechenclusters durch das Einbinden der Computer am Lehrstuhl in ein Linux-System zur Verteilung von Rechenprozessen über das Netzwerk ermöglichte die Bereitstellung der notwendigen Leistung zur Realisierung der Berechnungen. Es wurden Werkzeuge zur Modellierung der solvatisierten Aggregate von Peptiden ohne eindeutige Vorzugsstruktur programmiert und in ein Docking-System für beliebige Moleküle eingebunden. Verwendet wurde das Kraftfeld MMFF94 mit einer Erweiterung durch ein Verfahren zur dynamischen Berechnung von Partialladungen in Molekülstrukturen. Solvatisierte Aggregate der Dekapeptide und von bekannten amyloidbildenden Strukturen wurden modelliert (Docking). Berechnet wurden als aggregierend beschriebene Sequenzen und entsprechende Vergleichsstrukturen des Calcitonins, des Insel-Amyloid-Polypeptides, des beta2-Mikroglobulins, des Amyloid-beta-Proteins, des Lactoferrins und weitere Modellpeptide. Die wesentlichen Wechselwirkungen während der Aggregation konnten schließlich anhand von Dynamik-Simulationen der faltblattartigen Dimere des Cetrorelix und Ozarelix beschrieben werden. So wurden die Prozesse der hydrophoben Assoziation und Stabilisierung durch Wasserstoffbrücken von Peptiden veranschaulicht und auf molekularer Ebene erfolgreich analysiert. Die Visualisierung der erhaltenen Modellierungsergebnisse erfolgt durch die Darstellung der Strukturen und Dynamik-Simulationen als interaktive 3D-Modelle in einem für diese Arbeit aufgebauten Internetauftritt. / This work discusses the analysis of the aggregation properties of the gonadotropin releasing hormone antagonists Cetrorelix, Teverelix, Ozarelix and of small amyloid forming model peptides by analytical fluorescence spectroscopy and molecular modelling. A high performance linux compute cluster was developed for calculation of molecular structures. Solvated aggregate clusters of peptides without defined secondary structure were modelled by molecular mechanics methods (forcefield mmff94) in combination with an advanced charge equilibration and docking technique. Molecular dynamics of solvated peptide dimers were implemented and the role of hydrophic association and hydrogen bond formation in hydrophobic peptide aggregates was explained. Finally, an aggregation model for the directed association of hydrophobic peptides is presented. The modelling results, 3d structures and dynamic simulations are visualized in an interactive web material.