Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (p. 105-116).

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (p. 97-102).

To solve the programmability issue of membrane computing models, the automatic design of membrane systems is a newly initiated and promising research direction. In this paper, we propose an automatic design method, Permutation Penalty Genetic Algorithm (PPGA), for a deterministic and non-halting membrane system by tuning membrane structures, initial objects and evolution rules. The main ideas of PPGA are the introduction of the permutation encoding technique for a membrane system, a penalty function evaluation approach for a candidate membrane system and a genetic algorithm for evolving a population of membrane systems toward a successful one fulfilling a given computational task. Experimental results show that PPGA can successfully accomplish the automatic design of a cell-like membrane system for computing the square of n ( n >/= 1 is a natural number) and can find the minimal membrane systems with respect to their membrane structures, alphabet, initial objects, and evolution rules for fulfilling the given task. We also provide the guidelines on how to set the parameters of PPGA.

No description available.

While there have been many recently developed Elastic Network Models (ENM) to calculate the fluctuation dynamics of proteins, e.g., Gaussian Network Model (GNM), Anisotropic Network Model (ANM), Distance Network Model (DNM), the concept of loading these models to study the molecular mechanics and constitutive behavior of structural proteins has remained relatively untouched, until very recently. This work entails using the ANM as the framework for developing a finite element model of a 9–monomer strand of actin. Critical input parameters to the model, such as the cutoff radius, r[subscript c], and spring constant, k, are generated by matching the all-atom steered molecular dynamics (SMD) residue displacements to that of the ANM. The parameters yielding the best match between the SMD and structural ENM (SENM) simulations will then be input into the finite element model (FEM) for a more in depth analysis. The finite element model incorporates a 9–monomer strand of actin. The F–actin strand is subjected axial and torsional loads comparable to those seen in vivo. Key areas of interest in the protein are examined, such as the nucleotide binding pocket (NBP) and the DNase I binding loop, to demonstrate how loading affects the protein’s conformation. Local residue displacements are tracked in an effort to garner a better understanding of how various loads are transmitted through F–actin during key events. Insights and conclusions are discussed along with the implications of this work. / text

Results are presented from a variety of molecular simulations of phase coexistence using the well established Gay-Berne (GB) liquid crystal model. Firstly, the simulation of bulk phase coexistence using the Gibbs ensemble Monte Carlo technique is presented, both for one and two-component GB systems. The one-component results, using a novel parameterisation of the GB, show a rich phase behaviour, displaying both isotropic and nematic-vapour coexistence, in good comparison with previous studies. A method for arriving at the two-component parameterisation is then discussed, followed by a novel application of the Gibbs ensemble to the isotropic-nematic transition in two-component systems. Results in broad agreement with theoretical predictions, subject to a large finite size effect, are obtained. Secondly, upon the basis of the one-component Gibbs results, results are presented from a series of molecular dynamics simulations of a free standing GB film in equilibrium with its own saturated vapour. The introduction of inhomogeneity is shown to induce a preferred molecular alignment in the nematic film perpendicular to the liquid-vapour interface. At slightly higher temperatures the nematic film is wet by the isotropic phase, displaying an intermediate ordering regime where the formation of short-lived nematic domains within the film is observed. This effect has been analysed using orientational correlation functions, and shown to result from a decoupling of the planar and perpendicular nematic ordering caused by the system inhomogeneity. A system-size analysis of this effect has also been undertaken, showing a definite increase in the range of decay of these orientational correlations with increasing system size.

o processo de inclusão social do aluno portador de deficiência visual é facilitado pela adoção de estratégias pedagógicas, e pela utilização de materiais didáticos adequados. Neste trabalho, com o objetivo de facilitar a compreensão de conceitos químicos básicos, desenvolvemos um material didático, constituído de bolas texturizadas, que representam elementos qUlmlcos freqüentemente citados em aulas de Química de nível introdutório. Este material permite que o aluno, por meio do toque, e com o uso de uma legenda escrita em Braille, reconheça os elementos químicos em uma Tabela Periódica, especialmente montada para tal fim. Utilizando este modelo texturizado, o aluno pode, também, estabelecer ligações entre átomos, montar moléculas e cadeias de compostos orgânicos. Desta forma, a tridimensionalidade molecular pode ser melhor compreendida. O material instrucional foi testado com alunos de classes variadas, pertencentes à oitava série do ensino fundamental ou a uma das séries do ensino médio, sendo demonstrada sua eficiência. Além disso, em paralelo, procurou-se conhecer as idéias de professores, diretamente envolvidos com a educação especial, com relação à inclusão social de alunos deficiente visuais . / Special educational strategies and specific instructional material are needed in order to promote School and Social inclusion of students with visual impairment. In this work, we present our results on the development and testing of a new instructional material , composed of a specially designed Periodic Table of elements in which the na me of each element is written according to the Braille system, and some elements are represented by texturized balls. The tactile recognition of elements and names were very helpful in developing basic concept on chemical bonding and chemical properties of elements and compounds. Using texturized ball and stick models, High School students with visual impairment were also able to construct physical representations of organic and inorganic molecules, as well as of some hydrocarbon molecular chains. These three dimension structural models allowed for a proper insight on the space orientation of simple molecules. Some teachers\' ideas on the process of Social inclusion of students with visual impairment are also presented and discussed.

o processo de inclusão social do aluno portador de deficiência visual é facilitado pela adoção de estratégias pedagógicas, e pela utilização de materiais didáticos adequados. Neste trabalho, com o objetivo de facilitar a compreensão de conceitos químicos básicos, desenvolvemos um material didático, constituído de bolas texturizadas, que representam elementos qUlmlcos freqüentemente citados em aulas de Química de nível introdutório. Este material permite que o aluno, por meio do toque, e com o uso de uma legenda escrita em Braille, reconheça os elementos químicos em uma Tabela Periódica, especialmente montada para tal fim. Utilizando este modelo texturizado, o aluno pode, também, estabelecer ligações entre átomos, montar moléculas e cadeias de compostos orgânicos. Desta forma, a tridimensionalidade molecular pode ser melhor compreendida. O material instrucional foi testado com alunos de classes variadas, pertencentes à oitava série do ensino fundamental ou a uma das séries do ensino médio, sendo demonstrada sua eficiência. Além disso, em paralelo, procurou-se conhecer as idéias de professores, diretamente envolvidos com a educação especial, com relação à inclusão social de alunos deficiente visuais . / Special educational strategies and specific instructional material are needed in order to promote School and Social inclusion of students with visual impairment. In this work, we present our results on the development and testing of a new instructional material , composed of a specially designed Periodic Table of elements in which the na me of each element is written according to the Braille system, and some elements are represented by texturized balls. The tactile recognition of elements and names were very helpful in developing basic concept on chemical bonding and chemical properties of elements and compounds. Using texturized ball and stick models, High School students with visual impairment were also able to construct physical representations of organic and inorganic molecules, as well as of some hydrocarbon molecular chains. These three dimension structural models allowed for a proper insight on the space orientation of simple molecules. Some teachers\' ideas on the process of Social inclusion of students with visual impairment are also presented and discussed.

Les modèles physiques moléculaires sont depuis longtemps utilisés dans le domaine de la biologie structurale et de la chimie. Malgré l’apparition de représentations numériques qui offrent une grande variété de visualisations moléculaires dynamiques et permettent notamment d’analyser visuellement les résultats de simulations, les modèles physiques moléculaires sont encore fréquemment utilisés. En effet, la manipulation directe et la construction manuelle de modèles physiques moléculaires facilitent l’élaboration et la mémorisation d’une représentation mentale des structures moléculaires 3D. Les techniques d’interaction avec des objets 3D n’atteignent pas encore la finesse et la richesse de perception et de manipulation des modèles physiques. Par ailleurs, l’interaction avec des représentations moléculaires virtuelles est rendue particulièrement difficile car les structures moléculaires sont très complexes du fait de leur taille, de leur caractère tridimensionnel et de leur flexibilité, auquel s'ajoutent la quantité et la variété des informations qui les caractérisent. Pour aborder la problématique de l'interaction avec ces structures moléculaires, nous proposons dans cette thèse de concevoir une interface tangible moléculaire combinant les avantages des représentations physiques et virtuelles. Pour réaliser une interface tangible flexible et modulaire, à l’image des biomolécules à manipuler, ce travail de thèse a dû relever plusieurs défis scientifiques avec pour contrainte majeure le fait de proposer une approche se passant de marqueurs et dispositif de capture 3D complexe. La première étape fut de choisir, concevoir et fabriquer un modèle physique permettant la manipulation de molécules avec de nombreux degrés de libertés. La seconde étape consistait à créer un modèle numérique permettant de reproduire le comportement mécanique du modèle physique. Enfin, il a fallu concevoir des méthodes de recalage utilisant des techniques de traitement d'image en temps réel pour que le modèle physique puisse contrôler, par couplage, son avatar virtuel. En terme de traitement d’image, de nouvelles méthodes ont été conçues implémentées et évaluées afin d'une part, d’identifier et de suivre les atomes dans l’espace image et d'autre part, d'alimenter la méthode de reconstruction 3D avec un faible nombre de points. L'une de nos contributions a été d'adapter la méthode de Structure from Motion en incluant des connaissances biochimiques pour guider la reconstruction. Par ailleurs, la visualisation conjointe de modèles physiques de molécules et de leur avatar virtuel dynamique, parfois co-localisé dans un contexte de réalité augmentée, a été abordée. Pour cela, des méthodes de visualisation haute performance adaptées à ce contexte ont été conçues afin d’améliorer la perception des formes et cavités, caractéristiques importantes des molécules biologiques. Par exemple, l’occultation ambiante ou le raycasting de sphères avec des ombres portées dynamiques permettent d’augmenter un modèle physique en tenant compte de l’illumination réelle pour une meilleure intégration en réalité augmentée. Les retombées de ce travail en terme d’usage sont nombreuses dans le domaine de la recherche et de la pédagogie en biologie moléculaire, comme dans le domaine de la conception de médicaments et plus particulièrement du Rational Drug Design. L'expert doit être au centre de la tâche de conception de médicament pour la rendre plus efficace et rationnelle, à l’image du succès du jeu sérieux Fold’It, auquel s’ajoute le bénéfice de l’utilisation d’interface tangible capable de manipuler les nombreux degrés de liberté intrinsèques des biomolécules. / Physical molecular models have long been used in the structural biology and chemistry fields. Despite the emergence of numerical representations offering various and dynamic molecular visualizations to analyze the simulation results, molecular physical models are still being used. Direct manipulation and assembly of physical models ease to create and memorize a mental representation of 3D molecular structures. Interaction techniques to manipulate virtual 3D objects are not reaching the fineness and the benefits of the perceptual cues and manipulation skills of physical models. Moreover, interacting with virtual molecular representations remains a hard task because of the complexity of molecular structures, their size, their flexibility and the various data that define them. In this thesis, we address this issue by designing a molecular tangible interface combining the perks of physical and virtual representations. To match the flexibility and modularity of biomolecules to manipulate, this work met challenges in different scientific fields with the constraint to not use a tracker based system. The first step was to choose, conceive and build a physical model to handle the manifold degrees of freedom of molecules. The second step consisted in creating a numerical representation of mechanical properties of the physical model. Lastly, we needed to develop tracking methods using real-time image processing algorithms in order to control the virtual representation by coupling it to the physical one. New image processing methods have been implemented and evaluated to identify and track atoms in the image space. A Structure from Motion method was designed and adapted to reconstruct in 3D the atom positions by using a small amount of points and by including biochemical knowledge to guide the reconstruction. At last, we address the visualization of physical and dynamic virtual representations, sometimes co-localized in an Augmented Reality context. High performance visualization methods adapted to this context have been developed to enhance shape and cavity perception, two major specifics of biological molecules. For instance, ambient occlusion or sphere raycasting with dynamic shadows can augment a physical object taking the real illumination of the scene for a better insertion in an Augmented Reality context. The impact of this work targets both the education in molecular biology and the research field: the rational drug design field could benefit from the expertise of the user to optimize the design of drugs by manipulating biomolecule's numerous degrees of freedom using a tangible interface. Just like Fold'It is contributing to solve the folding problem, a similar approach could be used to solve the molecular docking problem using advanced manipulation interfaces.

This thesis describes a structure activity relationship (SAR) study on the recently discovered small molecule tool blebbistatin (S)-21 with particular emphasis on the development of novel synthetic protocols suitable for the rapid synthesis of libraries of blebbistatin analogues. These analogues are potentially of use as novel myosin inhibitors Chapter 1 introduces the concept of chemical biology with particular emphasis on chemical genetics. This approach has rekindled the search for new chemical tools for the investigation of biological systems. The success of blebbistatin (S)-21, which was identified in a chemical genetic study, as a research tool was also discussed. The link between several myosin classes and genetic diseases such as coeliac disease, Crohn’s disease, deafness, dermatitis, familial hypertrophic cardiomyopathy, Griscelli disease and ulcerative colitis indicate that potent inhibitors which show selectivity towards specific myosin isoforms may be of great value as tools for the study of these conditions. The plan for the SAR study around (S)-21 was outlined. Chapter 2 describes the studies undertaken to develop an efficient synthetic route to N1-alkyl analogues of (S)-21 suitable for the parallel synthesis of chemical collections. These studies culminated in the synthesis of an intermediate (S)-66 from which novel N1-alkyl analogues were synthesised. The biological evaluation of these N1-alkyl analogues was discussed. Chapter 3 describes the development of a protocol suitable for the parallel synthesis of collections of N1-aryl analogues of (S)-21 via the intermediate 66. The application of this protocol to the synthesis of a collection of racemic N1-aryl and heteroaryl analogues of (S)-21 and their biological evaluation was presented. Chapter 4 describes the successful rational design and synthesis of a novel fused thiophene ring containing inhibitor of myosin II. The structure of this compound was proposed by modelling of the existing co-crystal structure of (S)-21 bound to the metastable state of Dictyostelium discoideum myosin II (S1dC) and sought to optimise the π-π stacking interaction displayed by (S)-21 with the tyrosine 261 residue within its binding site. The biological evaluation of this novel analogue was discussed. In Chapter 5 the studies conducted to investigate the contribution of ring-C to the binding affinity of (S)-21 were described. The development of alternate routes to (S)-21, in an attempt to avoid difficulties experienced during the synthesis of some analogues of (S)-21, are described. The synthesis and biological investigation of the fluorescent dye PPBA whose binding site has been suggested to overlap with that of (S)-21 was also reported.