Neste trabalho, sondas solvatocrômicas foram empregadas no estudo de solventes puros, misturas aquosas de solventes próticos e apróticos, líquidos iônicos e suas misturas aquosas. As sondas estudadas foram agrupadas em duas séries, cujas mudanças relevantes foram: (i) série RPMBr2: R de metila a 1-octila permitiu a variação da hidrofobicidade da sonda enquanto o pKa se manteve constante; (ii) série de merocianinas derivadas de piridina, quinolina e acridina. Isso resultou em sondas de hidrofobicidades diferentes com valores parecidos de pKa. Desta forma foi possível isolar os efeitos sobre solvatação provocados pela hidrofobicidade das sondas. As duas séries de sondas mostraram comportamentos solvatocrômicos diferentes. Uma equação modificada de Taft-Kamlet-Abboud permitiu as quantificações individuais de cada propriedade do solvente, tais como acidez, dipolaridade/polarizabilidade e hidrofobicidade para a resposta de cada sonda. O modelo de solvatação preferencial que considera explicitamente a presença de três espécies na mistura binária de solvente foi aplicado, este considera que a água, o solvente orgânico e a espécie solvente orgânico-água competem pela camada de solvatação da sonda. Os resultados deste tratamento ajudaram no entendimento das forças atuantes na solvatação, especialmente com relação aos efeitos das propriedades de ambos a sonda e o solvente, e do aumento da temperatura. Estudos preliminares de misturas aquosas de líquidos iônicos mostraram as semelhanças e as diferenças entre a solvatação por estas misturas \"verdes\" e a por misturas aquosas de álcoois. Uma aplicação do solvatocromismo para o entendimento de un fenômeno físco-químico foi apresentada: os resultados da aplicação do modelo de solvatação preferencial de sondas em misturas aquosas de tetrametiluréia foram usados para explicar o fenômeno de gelificação de proteína neste mesmo sistema de solventes. / In the present work, solvatochromic probes were employed in the study of pure solvents, binary mixtures of water with protic and aprotic solvents, ionic liquids and their aqueous binary mixtures The probes studied are classified in two series: (i) RPMBr2; where R = methyl to 1-octyl allowed increasing the hydrophobicity while maintaining the pKa constant. (ii) The second series involved derivatives of pyridine, quinoline and acridine, this allowed increasing probe hydrophobicity, while maintaining similar pKa. The two series of probes showed different solvatochromic behaviors both in pure solvents and binary solvent mixtures. A modified equation of Taft-Kamlet-Abboud allowed quantification of each solvent property, including acidity, dipolarity/polarizability and hydrophobicity to the response of each probe. The preferential solvation model which explicitly considers the presence of three species was employed; it considers the competition of water, organic solvent and the complex water-organic solvent in the probe solvation shell. The results shed light on the interactions that affect solvation, including temperature-induced desolvation. Preliminary results on aqueous ionic liquids showed the similarities and difference between solvation by these \"green\" mixtures and those of aqueous alcohols. An application of solvatochromism for understanding a physical-chemical phenomenon was presented: the results of application of preferential solvation model of probes in aqueous tetramethylurea mixtures was used to explain the gelation of the protein lysozyme in this same solvent system.

<p>Metal ions solvated in aqueous, non-aqueous, and mixtures of solvents occur in many chemical contexts, for example in electrochemical applications and solvent separation. Solvated ions appear in high concentration in the living organisms, where their presence or absence can fundamentally alter the functions of life. In many of these cases, understanding the selective solvation and the dynamics of the ions is essential for the understanding of the processes involved.</p><p>Computer simulation provides a molecular level of detail of the solvation process usually not available from experiments. The quality of the interaction models employed in the theoretical description is of particular importance, since even rather small changes in the interaction can lead to substantial and qualitative differences.</p><p>This thesis describes the development of a sequence of increasingly refined analytical ion-solvent potentials from <i>ab initio</i> calculations for the systems Li⁺(<i>aq</i>), Na⁺(<i>aq</i>), Mg²⁺(<i>aq</i>), Al³⁺(<i>aq</i>), Li⁺(<i>MeCN</i>), Na⁺(<i>MeCN</i>), Li⁺(<i>aq, MeCN</i>), and Na⁺(<i>aq, MeCN</i>). Molecular dynamics simulations using these potentials were subsequently performed, and some key-properties computed. The reliability of the computed thermodynamical, structural and dynamical properties was scrutinized.</p>

<p>The aqueous solvation of metal ions is one of the long-standing and complex problems in chemistry, with implications for and applications in a broad range of biochemical and electrochemical systems, where water is the all-pervasive medium.</p><p>This thesis describes computer simulations of Al³⁺(<i>aq</i>), Fe²⁺(<i>aq</i>), Fe³⁺(<i>aq</i>) and Cu²⁺(<i>aq</i>). Various aspects of the solvation of these polyvalent metal ions in water are addressed, at different levels of theory, using Car-Parrinello molecular dynamics, classical molecular dynamics and quantum-mechanical cluster calculations. Polyvalent metal ions are particularly interesting because of their large influence on the solvent structure, dynamics and thermodynamics, as well as on the properties of the individual solvent molecules. Polyvalent metal ions in aqueous solution also constitute a challenging subject for computer simulations since a sophisticated interaction model is needed to incorporate the large many-body effects. </p><p>All the ion-water coordination figures in this thesis are octahedral, except in the Cu²⁺(<i>aq</i>) solution, where the ion is penta-coordinated with four equatorial neighbours in a plane and one axial neighbour located ~0.45 Å further out from the ion. The equatorial ion-water bonds have covalent character, while the axial water molecule is only electrostatically bound. For all the ions, the OD stretching frequencies of the first-shell water molecules are much more downshifted than in liquid water. In the case of Cu²⁺(<i>aq</i>), however, only the OD frequencies of the equatorial water molecules are downshifted with respect to bulk water whereas the OD frequencies of the axial water molecule are slightly upshifted. </p><p>Various limitations of the Car-Parrinello molecular dynamics simulations have been explored and compared, such as finite system-size effects and shortcomings in the electronic structure calculations. The Car-Parrinello simulations are found to give reasonable descriptions of the polyvalent metal ions in aqueous solution.</p>

<p>Aqueous solubility is a key parameter influencing the bioavailability of drugs and drug candidates. In this thesis computational models for the prediction of aqueous drug solubility were explored. High quality experimental solubility data for drugs were generated using a standardised protocol and models were developed using multivariate data analysis tools and calculated molecular descriptors. In addition, structural features associated with either solid-state limited or solvation limited solubility of drugs were identified.</p><p>Solvation, as represented by the octanol-water partition coefficient (log<i>P</i>), was found to be the dominant factor limiting the solubility of drugs, with solid-state properties being the second most important limiting factor.</p><p>The relationship between the chemical structure of drugs and the strength of their crystal lattice was studied for a dataset displaying log<i>P</i>-independent solubility. Large, rigid and flat molecules with an extended ring-structure and a large number of conjugated π-bonds were found to be more likely to have their solubility limited by a strong crystal lattice than were small, spherically shaped molecules with flexible side-chains.</p><p>Finally, the relationship between chemical structure and drug solvation was studied using computer simulated values of the free energy of hydration. Drugs exhibiting poor hydration were found to be large and flexible, to have low polarisability and few hydrogen bond acceptors and donors.</p><p>The relationship between the structural features of drugs and their aqueous solubility discussed in this thesis provide new rules-of-thumb that could guide decision-making in early drug discovery.</p>

<p>Information about protein structures is important in many areas of life sciences, including structure-based drug design. Gas phase methods, like electrospray ionization and mass spectrometry are powerful tools for the analysis of molecular interactions and conformational changes which complement existing solution phase methods. Novel techniques such as single particle imaging with X-ray free electron lasers are emerging as well. A requirement for using gas phase methods is that we understand what happens to proteins when injected into vacuum, and what is the relationship between the vacuum structure and the solution structure.</p><p>Molecular dynamics simulations in combination with experiments show that protein structures in the gas phase can be similar to solution structures, and that hydrogen bonding networks and secondary structure elements can be retained. Structural changes near the surface of the protein happen quickly (ns-µs) during transition from solution into vacuum. The native solution structure results in a reasonably well defined gas phase structure, which has high structural similarity to the solution structure. </p><p>Native charge locations are in some cases also preserved, and structural changes, due to point mutations in solution, can also be observed in vacuo. Proteins do not refold in vacuo: when a denatured protein is injected into vacuum, the resulting gas phase structure is different from the native structure.</p><p>Native structures can be protected in the gas phase by adjusting electrospray conditions to avoid complete evaporation of water. A water layer with a thickness of less than two water molecules seems enough to preserve native conditions.</p><p>The results presented in this thesis give confidence in the continued use of gas phase methods for analysis of charge locations, conformational changes and non-covalent interactions, and provide a means to relate gas phase structures and solution structures.</p>

No description available.

The aqueous solvation of metal ions is one of the long-standing and complex problems in chemistry, with implications for and applications in a broad range of biochemical and electrochemical systems, where water is the all-pervasive medium. This thesis describes computer simulations of Al3+(aq), Fe2+(aq), Fe3+(aq) and Cu2+(aq). Various aspects of the solvation of these polyvalent metal ions in water are addressed, at different levels of theory, using Car-Parrinello molecular dynamics, classical molecular dynamics and quantum-mechanical cluster calculations. Polyvalent metal ions are particularly interesting because of their large influence on the solvent structure, dynamics and thermodynamics, as well as on the properties of the individual solvent molecules. Polyvalent metal ions in aqueous solution also constitute a challenging subject for computer simulations since a sophisticated interaction model is needed to incorporate the large many-body effects. All the ion-water coordination figures in this thesis are octahedral, except in the Cu2+(aq) solution, where the ion is penta-coordinated with four equatorial neighbours in a plane and one axial neighbour located ~0.45 Å further out from the ion. The equatorial ion-water bonds have covalent character, while the axial water molecule is only electrostatically bound. For all the ions, the OD stretching frequencies of the first-shell water molecules are much more downshifted than in liquid water. In the case of Cu2+(aq), however, only the OD frequencies of the equatorial water molecules are downshifted with respect to bulk water whereas the OD frequencies of the axial water molecule are slightly upshifted. Various limitations of the Car-Parrinello molecular dynamics simulations have been explored and compared, such as finite system-size effects and shortcomings in the electronic structure calculations. The Car-Parrinello simulations are found to give reasonable descriptions of the polyvalent metal ions in aqueous solution.

Aqueous solubility is a key parameter influencing the bioavailability of drugs and drug candidates. In this thesis computational models for the prediction of aqueous drug solubility were explored. High quality experimental solubility data for drugs were generated using a standardised protocol and models were developed using multivariate data analysis tools and calculated molecular descriptors. In addition, structural features associated with either solid-state limited or solvation limited solubility of drugs were identified. Solvation, as represented by the octanol-water partition coefficient (logP), was found to be the dominant factor limiting the solubility of drugs, with solid-state properties being the second most important limiting factor. The relationship between the chemical structure of drugs and the strength of their crystal lattice was studied for a dataset displaying logP-independent solubility. Large, rigid and flat molecules with an extended ring-structure and a large number of conjugated π-bonds were found to be more likely to have their solubility limited by a strong crystal lattice than were small, spherically shaped molecules with flexible side-chains. Finally, the relationship between chemical structure and drug solvation was studied using computer simulated values of the free energy of hydration. Drugs exhibiting poor hydration were found to be large and flexible, to have low polarisability and few hydrogen bond acceptors and donors. The relationship between the structural features of drugs and their aqueous solubility discussed in this thesis provide new rules-of-thumb that could guide decision-making in early drug discovery.

Accurate calculations of free energies for molecular association and solvation are important for the understanding of biochemical processes, and are useful in many pharmaceutical applications. In this thesis, molecular dynamics (MD) simulations are used to calculate thermodynamic properties for solvation and ligand binding. The thermodynamic integration technique is used to calculate pKa values for three aspartic acid residues in two different proteins. MD simulations are carried out in explicit and Generalized-Born continuum solvent. The calculated pKa values are in qualitative agreement with experiment in both cases. A combination of MD simulations and a continuum electrostatics method is applied to examine pKa shifts in wild-type and mutant epoxide hydrolase. The calculated pKa values support a model that can explain some of the pH dependent properties of this enzyme. Development of the linear interaction energy (LIE) method for calculating solvation and binding free energies is presented. A new model for estimating the electrostatic term in the LIE method is derived and is shown to reproduce experimental free energies of hydration. An LIE method based on a continuum solvent representation is also developed and it is shown to reproduce binding free energies for inhibitors of a malaria enzyme. The possibility of using a combination of docking, MD and the LIE method to predict binding affinities for large datasets of ligands is also investigated. Good agreement with experiment is found for a set of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Approaches for decomposing solvation and binding free energies into enthalpic and entropic components are also examined. Methods for calculating the translational and rotational binding entropies for a ligand are presented. The possibility to calculate ion hydration free energies and entropies for alkali metal ions by using rigorous free energy techniques is also investigated and the results agree well with experimental data.

This thesis describes the development of a generic model for predicting the emissions of organic compounds from materials used in the manufacture of various goods and products. Many products contain organic substances that are not bound to the matrix formed by their constituent materials and are thus able to dissociate from the material and become transferred into the surrounding environment. A wide range of materials and products are used in modern societies, and many compounds deriving from these materials are regarded as emerging pollutants in both indoor and outdoor environments. The model uses three components to describe the transfer of compounds from materials to the surrounding environment: partitioning of the compound between the material and its surroundings based on linear free energy relationships, diffusion within the material based on the Piringer equation, and convective mass transfer in air or water based on an empirical flat surface model. The model’s predictive capacity was tested against three experimental case studies: emissions of plasticizers from vinyl flooring and triphenyl phosphate from LCD screens into the air, and leaching of organophosphates from concrete into water. The rates of emission from vinyl flooring were clearly affected by the number of layers comprising the material. Triphenyl phosphate was found in the front surface of all tested flat screens and its rates of emission were related to the nature of the screen and its operating temperature. The model accurately predicted emissions into the air and leaching from concrete into water once modified to include modules that describe dissolution from surfaces and diffusion in water-filled pores. The model was then used to investigate emissions on the national scale. It was found that the rates of emission from vinyl flooring are not changing over time, and that the total mass of emitted material is dependent on annual sales volumes and the expected life span of the vinyl flooring. Moreover, the additive used has a large effect on the emitted mass. Emissions from flat screen displays depend strongly on their operating temperatures: displays with high working temperatures that are active for extended periods of time produce more emissions. The model was also used to study the release of organophosphates from the concrete used to make a bridge, which depended on the flow of water under the bridge, the temperature, the porosity of the concrete, and the additive’s water solubility. Data on annual sales volumes and the total surface area of sold goods are essential when studying emissions on a national scale. National retailers’ organizations are valuable sources of such information. When adequate data are not available, it is necessary to perform uncertainty analyses to determine the impact of uncertainty in the modeling of different stages of the emissions process in different scenarios.