The development and approval of new drugs is an expensive process. The total cost for the approval of a new compound is on average 1.0 - 1.2 billion dollars and the entire process lasts about 12 - 15 years. The main difficulties are related to poor pharmacokinetics, lack of efficacy and unwanted side effects. These problems have naturally led to the question if new and alternative methodologies can be developed to find reliable and low cost alternatives to existing practices. Nowadays, computer-assisted tools are used to support the decision process along the early stages of the drug discovery path leading from the identification of a suitable biomolecular target to the design/optimization of drug-like molecules. This process includes assessments about target druggability, screening of molecular libraries and the optimization of lead compounds where new drug-like molecules able to bind with sufficiently affinity and specificity to a disease-involved protein are designed. Existing computational methods used by the pharmaceutical industry are usually focused on the screening of library compounds such as docking, chemoinformatics and other ligand-based methods to predict and improve binding affinities, but their reliable application requires improvements in accuracy. New quantitative methods based on molecular simulations of drug binding to a protein could greatly improve prospects for the reliable in-silico design of new potent drug candidates. A common parameter used by medicinal chemists to quantify the affinity between candidate ligands and a target protein is represented by the free energy of binding. However, despite the increased amount of structural information, predicting binding free energy is still a challenge and this technique has found limited use beyond academia. A major reason for limited adoption in the industry is that reliable computer models of drug binding to a protein must reproduce the change in molecular conformations of the drug and protein upon complex formation and this includes the correct modelling of weak non-covalent interactions such as hydrogen bonds, burials of hydrophobic surface areas, Van der Waals interactions, fixations of molecular degrees of freedom solvation/desolvation of polar groups and different entropy contributions related to the solvent and protein interactions. For several classes of proteins these phenomena are not easy to model and often require extremely computationally intensive simulations. The main goal of the thesis was to explore efficient ways of computing binding affinities by using molecular simulations. With this aim, novel software to compute relative binding free energies has been developed. The implementation is based on alchemical transformations and it extended a preexisted piece of software Sire, a molecular modeling framework, by using the OpenMM APIs to run fast molecular dynamics simulations on the latest GPGPU technology. This new piece of software has equipped the scientific community with a flexible and fast tool, not only to predict relative binding affinities, but also a starting point to develop new sampling methods for instance hybrid molecular dynamics and Monte Carlo. The implementation has been validated on the prediction of relative hydration free energy of small molecules, showing good agreement with experimental data. In addition, non-additive effects to binding affinities in series of congeneric Thrombin inhibitors were investigated. Although excellent agreement between predicted and experimental relative binding affinities was achieved, it was not possible to accurately predict the non-additivity levels in most of the examined inhibitors, thus suggesting that improved force fields are required to further advance the state-of-the art of the field.

O objetivo dessa pesquisa foi analisar um jogo didático intitulado Autódromo Alquímico e como esse tipo de metodologia pode contribuir para o Ensino de Química. As hipóteses de trabalho a priori são que atividades lúdicas e jogos desse tipo podem (i) favorecer a motivação dos alunos e o interesse dos mesmos em aprender (ii) desenvolver nos educandos habilidades cognitivas através das Funções Psicológicas Superiores (FPS) tais como: Emoção, Imaginação, Percepção, Atenção, Memória, Pensamento, Linguagem, Abstração e Generalização, por fim,(iii) possibilitar a significação e o aprofundamento do conhecimento a respeito da Alquimia e da Química. A pesquisa foi realizada na perspectiva do método de análise qualitativa, sendo desenvolvida nos moldes do estudo de caso. O Referencial Teórico utilizado e em relação à função do jogo é baseado em Vygotsky e seus alunos, Leontiev e Elkonin principalmente. A atividade lúdica trabalhada foi o Jogo Autódromo Alquímico e todas as suas etapas de aplicação inseridas no contexto da Educação em Química. Os colaboradores do trabalho foram 263 estudantes de nove turmas do 9º ano do Ensino Fundamental de uma escola particular da cidade de Itabuna no estado da Bahia. A obtenção dos dados foi realizada através de análises diagnósticas (iniciais, continuadas e finais) com perguntas abertas, além de filmagens digitais e entrevistas com os educandos sendo, posteriormente, tratados com a utilização de ferramentas da análise de conteúdo. Os resultados encontrados corroboraram as três hipóteses (i) (ii) e (iii). Os dados encontrados demonstraram existir uma relação direta entre a aplicação da atividade lúdica e uma maior ressignificação e aprofundamento do conhecimento em Química. Conclui-se que o Jogo foi benéfico para o processo de ensino e aprendizagem em Ciências, pois houve aprendizagem e ressignificação do conhecimento da Alquimia e da Química. Também foi perceptível o desenvolvimento de várias habilidades apontadas como importantes para a formação de um cidadão crítico e reflexivo. / The objective of this research was to analyze a didactic game titled Alchemical Speedway and how such a methodology can help to teach chemistry. Working hypotheses are that play activities and games of that type may (i) foster students\' motivation and interest in learning the same (ii) to develop in students the higher psychological functions (FPS) such as: Emotion, Imagination, Perception, Attention, Memory, Thought, Language, Abstraction and Generalization, finally, (iii) enable the significance and deepen the knowledge of alchemy and chemistry. The survey was conducted in view of the method of qualitative analysis, being developed as a case study. The theoretical basis and in relation to the function of the game is based on Vygotsky and his students, Leontiev and Elkonin mainly. Leisure activity was crafted game Alchemical Speedway and all stages of application placed in the context of Education in Chemistry. Employees of the study were 204 students from nine classes in 9th grade of elementary school to a private school in the city of Itabuna in the state of Bahia. Data collection was performed through diagnostic tests (initial, continuing and final) with open questions, in addition to digital footage and interviews with the students and subsequently treated with the use of tools of content analysis. The results corroborate the three hypotheses (i) (ii) and (iii). The data showed a direct relationship exists between the application of leisure activity and a major reframing and deepening of knowledge in chemistry. We conclude that the game was beneficial to the process of teaching and learning in science, because there was learning the knowledge of Alchemy and Chemistry. Also noticeable was the development of various skills identified as important for the formation of a critical and reflective citizen.

O objetivo dessa pesquisa foi analisar um jogo didático intitulado Autódromo Alquímico e como esse tipo de metodologia pode contribuir para o Ensino de Química. As hipóteses de trabalho a priori são que atividades lúdicas e jogos desse tipo podem (i) favorecer a motivação dos alunos e o interesse dos mesmos em aprender (ii) desenvolver nos educandos habilidades cognitivas através das Funções Psicológicas Superiores (FPS) tais como: Emoção, Imaginação, Percepção, Atenção, Memória, Pensamento, Linguagem, Abstração e Generalização, por fim,(iii) possibilitar a significação e o aprofundamento do conhecimento a respeito da Alquimia e da Química. A pesquisa foi realizada na perspectiva do método de análise qualitativa, sendo desenvolvida nos moldes do estudo de caso. O Referencial Teórico utilizado e em relação à função do jogo é baseado em Vygotsky e seus alunos, Leontiev e Elkonin principalmente. A atividade lúdica trabalhada foi o Jogo Autódromo Alquímico e todas as suas etapas de aplicação inseridas no contexto da Educação em Química. Os colaboradores do trabalho foram 263 estudantes de nove turmas do 9º ano do Ensino Fundamental de uma escola particular da cidade de Itabuna no estado da Bahia. A obtenção dos dados foi realizada através de análises diagnósticas (iniciais, continuadas e finais) com perguntas abertas, além de filmagens digitais e entrevistas com os educandos sendo, posteriormente, tratados com a utilização de ferramentas da análise de conteúdo. Os resultados encontrados corroboraram as três hipóteses (i) (ii) e (iii). Os dados encontrados demonstraram existir uma relação direta entre a aplicação da atividade lúdica e uma maior ressignificação e aprofundamento do conhecimento em Química. Conclui-se que o Jogo foi benéfico para o processo de ensino e aprendizagem em Ciências, pois houve aprendizagem e ressignificação do conhecimento da Alquimia e da Química. Também foi perceptível o desenvolvimento de várias habilidades apontadas como importantes para a formação de um cidadão crítico e reflexivo. / The objective of this research was to analyze a didactic game titled Alchemical Speedway and how such a methodology can help to teach chemistry. Working hypotheses are that play activities and games of that type may (i) foster students\' motivation and interest in learning the same (ii) to develop in students the higher psychological functions (FPS) such as: Emotion, Imagination, Perception, Attention, Memory, Thought, Language, Abstraction and Generalization, finally, (iii) enable the significance and deepen the knowledge of alchemy and chemistry. The survey was conducted in view of the method of qualitative analysis, being developed as a case study. The theoretical basis and in relation to the function of the game is based on Vygotsky and his students, Leontiev and Elkonin mainly. Leisure activity was crafted game Alchemical Speedway and all stages of application placed in the context of Education in Chemistry. Employees of the study were 204 students from nine classes in 9th grade of elementary school to a private school in the city of Itabuna in the state of Bahia. Data collection was performed through diagnostic tests (initial, continuing and final) with open questions, in addition to digital footage and interviews with the students and subsequently treated with the use of tools of content analysis. The results corroborate the three hypotheses (i) (ii) and (iii). The data showed a direct relationship exists between the application of leisure activity and a major reframing and deepening of knowledge in chemistry. We conclude that the game was beneficial to the process of teaching and learning in science, because there was learning the knowledge of Alchemy and Chemistry. Also noticeable was the development of various skills identified as important for the formation of a critical and reflective citizen.

With advancements in computer technology and processing power, the ability to examine chemical systems using theory continues to be more practicable. Using ab initio methods, such as density functional theory, we are now able to routinely simulate hundreds of atoms. This system size allows us to directly simulate surfaces and nano-materials that are industrially relevant. With the expansion of accessible systems comes the opportunity to develop new computational methods to extract their chemical properties. Of particular interest is bridging the time scale gap between simulation and experiment. The evolution of a system chemical in time can be directly simulated using classical dynamics, however, molecules vibrate on the order of femtoseconds and interesting transitions tend to happen on much longer time scales: milliseconds to seconds. In condensed phase chemical systems these interesting transitions are hindered by energy barriers so state to state dynamics are dominated by rare evens. Luckily, rare event transitions tend to happen through mountain passes in the potential energy landscape. Within harmonic transition state theory, the transition states between minima can be characterized by saddle points. Finding saddle points is a challenging problem which has not been satisfactorily solved; nevertheless, there are algorithms currently being used despite their deficiency. In particular, my work strives to improve the efficiency and stability of the nudged elastic band method and compare its performance to similar algorithms on a variety of test systems. In addition, I present a method to predict how energy-based chemical properties change with respect to the chemical composition of the system. This is achieved by taking a derivative of the property with respect to the atomic numbers of the atoms present in the system. The accuracy and predictive quality of these derivatives are assessed for both model and industrially relevant systems. With this information, we can follow these derivatives to optimize a desired property in the space of chemical composition. This method is a step toward using theory to rationally design compounds with desirable properties. / text

Qualifiée d’« oeuvre steganographique » par son auteur, L’Histoire veritable ou Le Voyage des princes fortunez (1610) inaugure le roman alchimique en France en réactivant le modèle littéraire de l’Hypnerotomachia Poliphili « alchimisé » par Nazari et Gohory, puis édité par Béroalde de Verville (1556-1626) en 1600. Longtemps méconnu, il est redécouvert par E. Vordemann (1933) qui identifie sa source principale, traduction italienne de contes orientaux, le Peregrinaggio di tre figliuoli del re di Serendippo, de Cristoforo Armeno (1557). Eclairée par les recherches béroaldiennes qui ont suivi l’étude fondatrice de V.-L. Saulnier, notre thèse propose une édition commentée du roman qui met en valeur de nombreuses sources, le contexte de la genèse de l’oeuvre et ses modèles littéraires. La mise en fiction de l’alchimie s’articule avec la conception rationnelle ou grivoise de cet art chez Béroalde, écrivain polygraphe et médecin alchimiste. On assiste ainsi au renouvellement de l’écriture romanesque stimulant par ses jeux une « juste curiosité » du lecteur. L’étude met enfin en regard deux textes plus politiques de Béroalde, son poème L’Idée de la république (1584) et son discours anonyme, De la guerre (1589). / Described as an « oeuvre steganographique » by its author, L’Histoire veritable ou Le Voyage des princes fortunez (1610) opens the way to alchemical novel in France, by reactivating the literary model of Hypnerotomachia Poliphili, « alchemized » by Nazari and Gohory before being edited by Beroalde de Verville (1556-1626), in 1600. Left in the dark for a long time, it was rediscovered by E. Vordemann (1933) who identified its main source, an Italian translation of Eastern tales, Peregrinaggio di tre figliuoli del re di Serendippo, by Cristoforo Armeno (1557). Enlightened by the essays on Beroalde, which followed the pioneering study by V.-L. Saulnier, our thesis provides a critical edition that reveals many sources, its genesis’ context and its literary models. The study shows how the fictional motif of alchemy deals with the scientific or bawdy conception of this art in the work of Beroalde, a polygraph writer and an alchemist doctor, and also how it renews the novelistic way of writing by stimulating a « juste curiosité » with its games. At last, it compares two texts by Beroalde, considered more political, his poem L’Idée de la république (1584), and his anonymous discourse, De la guerre (1589).

Made available in DSpace on 2016-04-28T14:16:17Z (GMT). No. of bitstreams: 1 Reno Stagni.pdf: 17589339 bytes, checksum: db482e5e34a0e806a35d91addaec3478 (MD5) Previous issue date: 2013-06-07 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This paper Will present the scientific facts discussed in the book Conversations on the Plurality of Worlds, written by Bernard Le Boyer de Fontenelle, in 1686, which had a great impact on many issues. To narrate the scientific facts of the time, Fontenelle deals, the book first published in 1686, the form of dialogues between supposedly caught him and a marquese on their evening walks around the castle gardens in the Summer. Both talk about the design of astronomical systems from Ptolomy and Copernicus. The Moon, the planets and the possibility of existence of other worlds like our own, are also discussed during the meetings. Narratives built using a communications strategies and arguments in order to facilitate understanding of abstract and complex astronomical phenomena by means of analogies. With the book, takes part in iniciatives to popularize science, in order to inform and entertain people without impose theories, staying somewhat on the fringes of science academies. In this paper we present the ideas of science contained in the book, trying to recognize, at the same time, the similarities and differences of those groups conveyed by scholars / Este trabalho apresentará os fatos científicos discutidos no livro Diálogos sobre a Pluralidade dos Mundos, escrito por Bernard Le Boyer de Fontenelle, em 1686, que teve grande repercussão com grande número de edições. Para narrar os fatos científicos da época, Fontenelle adota a forma de diálogos supostamente travados entre ele e uma marquesa em seus passeios noturnos pelos jardins do castelo, no verão. Os dois conversam sobre a concepção dos sistemas astronômicos de Ptolomeu e Copérnico. A Lua, os planetas e a possibilidade de existência de outros mundos semelhantes ao nosso, também são tratados durante os encontros. Fontenelle construiu narrativas utilizando estratégias de comunicação e argumentação, de modo a facilitar a compreensão dos fenômenos astronômicos abstratos e complexos por meio de analogias, Com o livro, toma parte de iniciativas em divulgar a ciência, com o intuito de informar e entreter as pessoas, sem impor teorias, mantendo-se, de certa forma, à margem da ciência das academias. Neste trabalho vamos apresentar as ideias de ciência contidas no livro, buscando reconhecer, ao mesmo tempo, as aproximações e distanciamentos daquelas veiculadas pelos grupos eruditos

[pt] O coeficiente de partição octanol-água do composto 1,2-dipalmitoilsn-glicero-3-fosfatidilcolina (DPPC) foi investigado utilizando os métodos de integração termodinâmica e amostragem guarda-chuva através de simulações de dinâmica molecular atomística. Os campos de força AMBER/GAFF e CHARMM/CGenFF foram usados com seis modelos de água (SPC, TIP3P, TIP4P, TIP5P, OPC3 e OPC4) amplamente utilizados em simulações de dinâmica molecular. Dentre os modelos utilizados, o modelo de água OPC4 com os dois campos de força em estudo forneceu a melhor concordância com o coeficiente de partição experimental octanol-água do DPPC. No entanto, ainda existe muito espaço para melhorias nos modelos de água que estimam a tensão superficial de forma apropriada. Usando o modelo de água OPC4, a energia livre de Gibbs de transferência do DPPC do octanol para a fase aquosa foi calculada em 19,8(mais ou menos)0,3 e 20,2(mais ou menos)0,3 kcal mol-1 , estimando um coeficiente de partição octanol-água de 14,5(mais ou menos)0,4 e 14,8(mais ou menos)0,3 para os campos de força AMBER/GAFF e CHARMM/CGenFF, respectivamente. A amostragem guarda-chuva apresentou problemas de arrastes de moléculas de uma fase para outra, gerando artefatos e consequentemente subestimando os valores de energia livre e de coeficiente de partição octanol-água. Este estudo mostra a importância do desenvolvimento de novos modelos de água que reproduzam com precisão todas as suas características experimentais. A conciliação entre medições experimentais e cálculos teóricos do coeficiente de partição de moléculas anfifílicas poderia ser resolvida através do ajuste dos parâmetros do modelo de água. Este estudo possui grande importância na simulação de propriedades moleculares de importância em muitas áreas de aplicações científicas e industriais, tais como biofísica, surfactante, coloides, membranas, medicina, nanotecnologia, e indústrias alimentícias e farmacêuticas. / [en] The octanol-water partition coefficient of the compost 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) molecule wasinvestigated using the methods of thermodynamic integration and umbrellasampling through atomistic molecular dynamics simulations. TheAMBER/GAFF and CHARMM/CGenFF force fields were used with sixwater models (SPC, TIP3P, TIP4P, TIP5P, OPC3, and OPC4) widely usedin molecular dynamics simulations. Among the models used, the OPC4water model with the two force fields provided the best agreement with theexperimental octanol-water partition coefficient of the DPPC. However,there is still much room for improvement in water models that correctlyestimate the surface tension. Using the OPC4 water model, the Gibbs freeenergy of transferring DPPC from octanol to the aqueous phase wascalculated to be 19.8(plus minus)0.3 and 20.2(plus minus)0.3 kcal mol-1, estimating an octanolwater partition coefficient of 14.5(plus minus)0.4 and 14.8(plus minus)0.3 for the AMBER/GAFFand CHARMM/CGenFF force fields, respectively. Umbrella samplingpresented issues of molecules being dragged between the two phases,generating artifacts, and consequently underestimating the values of freeenergy and octanol-water partition coefficient. This study shows theimportance of developing new models of water that accurately reproduceall its experimental characteristics. The reconciliation betweenexperimental measurements and theoretical calculations of partitioncoefficients of amphiphilic molecules. This study may have greatimportance in many areas of scientific and industrial applications, such asbiophysics, surfactant, colloids, membranes, medicine, nanotechnology,and food and pharmaceutical industries.