¡@¡@Wire bonding has been used in integrated circuit packaging for many years which has been more full-grown than other bonding methods, and gold wire has been the preferred choice. Because of the rising price of gold every year, copper wire has been increasingly used to replace gold wire. ¡@¡@The main focus of this paper is to simulate 3D copper-Al pad thermosonic wire bonding stage by using 3D finite element method. Firstly, the differences between mechanical analysis (the thermal effect was not considered) and thermo-mechanical coupling analysis from both impact stage and ultrasonic vibration stage, respectively, were compared. Secondly, the differences between copper thermosonic wire bonding analysis and gold thermosonic wire bonding analysis were discussed. Finally, the effects of Al pad thickness variation on the copper thermosonic wire bonding analysis were studied. ¡@¡@Results showed that, due to the mechanical properties will be decreased by thermal effects caused from temperature increasing, the obtained effective stress and efective strain of thermo-mechanical coupling analysis were less than the results obtained from mechanical analysis. The pad plastic defomation in copper thermosonic wire bonding is more critical than gold thermosonic wire bonding. Therefore, copper thermosonic wire bonding will lead to serious pad splashing. Also, quantity of the decreasing of pad plastic deformation was limited by increasing the pad thickness.

In this work, a new method is suggested for the modal identification of nonlinear structures and for the use of the modal data in calculating response of the nonlinear system to harmonic excitation. Nonlinearity in mechanical structures is usually encountered in connection regions. In this study, the nonlinear part of such a structure is modeled as a single nonlinear element and modal parameters of the structure are obtained as a function of displacement amplitude. Identification and modeling of nonlinear elements can be done through modal tests conducted at different response levels. Response level dependent modal parameters are used in calculating the response of the system to harmonic excitation at any forcing level. Furthermore, the modal model of a nonlinear substructure can be used in structural coupling of the nonlinear system with a linear one, and in structural modification problems where a nonlinear structure is modified with linear elements. Validation of the modal model proposed, and the use of this model in harmonic response computation, structural coupling and structural modification problems are demonstrated with several case studies.

The prokaryotic Erwinia chrysanthemi ligand-gated ion channel (ELIC) is competitively inhibited by acetylcholine (Pan et al., 2012). Acetylcholine is the native agonist of the structurally related family of eukaryotic acetylcholine receptors, which like ELIC are pentameric ligand-gated ion channels. To understand the opposite effect upon acetylcholine binding between ELIC and acetylcholine receptors, we used statistical coupling analysis to predict mutations necessary for installing acetylcholine agonism into ELIC. Statistical coupling analysis was performed on the acetylcholine binding protein from Lymnaea stagnalis. This protein is a structural surrogate for the agonist binding domain of acetylcholine receptors, for which a high-resolution structure in complex with acetylcholine is available. Our analysis identified a group of statistically coupled residues that comprises several amino acids previously implicated in acetylcholine agonism of acetylcholine receptors. Mapping these residues onto ELIC revealed 15 residue discrepancies, 4 of which were chosen for initial mutagenesis based upon their proximity to the known agonist binding site. Electrophysiological characterization of ELIC mutants indicates that the potency of the native agonist, cysteamine, is decreased, highlighting the optimized role wild-type residues serve in native agonism. None of the mutants were activated by acetylcholine, however the double mutant A75D/F133W abolished competitive antagonism by acetylcholine, and instead led to acetylcholine dependent potentiation of cysteamine-induced currents. This work demonstrates the ability of statistical coupling analysis to identify functionally important residues in pentameric ligand-gated ion channels and reveals that acetylcholine can be converted from a competitive antagonist into a potentiator, by installing two residues present in acetylcholine receptors.

Les travaux entrepris au cours de cette thèse ont permis de concevoir des stratégies de commande de systèmes multivariables (outils d’analyse et méthodes de synthèse) en vue de leur application au développement de lois de commande d’un turbopropulseur.D’un point de vue fonctionnel, un turbopropulseur est un système multivariable comprenant deux grandeurs de commande : le débit carburant à injecter dans la chambre de combustion et le pas de l’hélice, ainsi que deux grandeurs de sortie : la puissance délivrée par l’hélice et sa vitesse de rotation. Ces variables sont fortement couplées, ce qui signifie que des variations de l’une entraînent des écarts sur l’autre. L’objectif de ces travaux est de synthétiser des lois de commande facilement ajustables, permettant de respecter des spécifications classiques en Automatique (temps de réponse, dépassement, erreur statique) et de réduire les couplages entre les différentes grandeurs régulées. Dans ce contexte industriel, les approches décentralisées sans et avec découplage sont envisagées. La stratégie décentralisée pure met en œuvre un correcteur diagonal, ce qui revient à asservir un système par plusieurs boucles monovariables indépendantes. Bien que relativement facile à synthétiser et à implanter, la stratégie décentralisée ne permet pas d’atteindre les performances souhaitées en présence d’interactions importantes. Dans ce cas, il est possible de l’associer à des compensateurs permettant de diminuer les interactions.Une part importante de ces travaux de recherche concerne le développement méthodologique de ces stratégies. La définition d’une stratégie de commande est la première étape. Pour cela, la quantification du niveau d’interaction dans un système se révèle importante. Celle-ci peut être réalisée à l’aide de différentes méthodes et indicateurs qui s’appuient sur les réponses fréquentielles ou temporelles du système, ou encore sur les grammiens de commandabilité et d’observabilité. Une procédure systématique d’analyse des interactions a été proposée afin de déterminer la stratégie de commande la plus adaptée en fonction des interactions. Dans le cas où l’analyse des interactions conduit à adopter une stratégie décentralisée, les régulateurs peuvent être synthétisés à l’aide de méthodes monoboucles ou multiboucles. Les premières ne prennent pas en compte les interactions tandis que les secondes, plus élaborées mais également plus complexes à mettre en œuvre, permettent de les prendre spécifiquement en compte. A la suite de l’analyse de ces méthodes, une étude récapitulative présentant les méthodes préconisées en fonction du procédé et des objectifs, est finalement proposée. Dans le cas où l’analyse des interactions montre un niveau de couplage trop important, il est possible d’associer des compensateurs à la régulation décentralisée. Les compensateurs ont pour but de découpler les commandes vis-à-vis des sorties du procédé. Différentes méthodes et structures de découplage ont été étudiées et comparées. Une procédure de découplage, composée des méthodes considérées comme les plus efficaces a finalement été mise en place. / In this Ph.D. thesis, we explore the different steps of designing a decentralized control applied on a turboprop engine.From the control point of view, the turboprop engine is a TITO (Two-Input Two-Output) process. The fuel flow is used to control the shaft power while the blade pitch angle is used to control the propeller speed. The turboprop presents important couplings between manipulated variables and controlled variables. When the fuel flow changes, the propeller speed is impacted. Similarly, when controlling the blade pitch angle to change the propeller speed to another level, the shaft power is affected, particularly during the transient states. The main objective of this research thesis is to design control laws for the turboprop. Beside technical specifications like response time and overshoot, couplings between loops have to be reduced as much as possible and control laws have to be robust to model uncertainties. For this industrial environment a decentralized strategy (with or without compensators) has been chosen. The decentralized strategy consists in designing monoloop controllers in order to drive the multivariable system. The decentralized strategy presents important benefits, such as flexibility as well as design simplicity, but is not efficient in presence of heavy couplings. In that case, it is possible to use compensators that reduce existing process interactions before designing the monoloop controllers.An important part of this work focuses on the development of these different strategies.The first step is the choice of the control structure, which strongly depends on the level of interaction. Despite the availability of different metrics - based on frequential responses, temporal responses, or Gramian – it is not easy to know which one is the most appropriate. Based on the analysis of couplings with different metrics, a procedure is proposed in order to choose the structure and the controllers design method.If the coupling analysis leads to adopt a decentralized strategy, the controllers can be designed using monoloop or multiloop methods. The first ones are simple but do not take couplings into account, whereas multiloop methods take specifically couplings into account but are more complicated. These tuning methods have been studied and recommendations have finally been made to choose the most appropriated method depending on the process and the requirements.In cases where the couplings analysis reveals a high couplings level, compensators can be associated with the decentralized strategy. The objectives of the compensators are to reduce couplings in the system and to facilitate the design of monoloop controllers. Several decoupling structures have been studied and compared. A decoupling procedure has then been proposed.These methodological studies have been applied to the turboprop engine. Following the coupling analysis, a decentralized strategy with decoupling has been chosen. After following the decoupling procedure and trying different solutions, the inverted decoupler has been adopted. Considering the dynamics of the system and the total decoupling provided by the inverted decoupler, PI controllers have been used and a monoloop tuning method has been chosen. In order to guarantee the desired performances over the whole flight envelope, control laws have been interpolated, using a gain scheduling technique. The structured singular value approach has then been used to demonstrate the robustness of the control laws with model uncertainties. Control laws have finally been implemented in the control software and simulation results have illustrated their good performances.

Les travaux entrepris au cours de cette thèse ont permis de concevoir des stratégies de commande de systèmes multivariables (outils d’analyse et méthodes de synthèse) en vue de leur application au développement de lois de commande d’un turbopropulseur.D’un point de vue fonctionnel, un turbopropulseur est un système multivariable comprenant deux grandeurs de commande : le débit carburant à injecter dans la chambre de combustion et le pas de l’hélice, ainsi que deux grandeurs de sortie : la puissance délivrée par l’hélice et sa vitesse de rotation. Ces variables sont fortement couplées, ce qui signifie que des variations de l’une entraînent des écarts sur l’autre. L’objectif de ces travaux est de synthétiser des lois de commande facilement ajustables, permettant de respecter des spécifications classiques en Automatique (temps de réponse, dépassement, erreur statique) et de réduire les couplages entre les différentes grandeurs régulées. Dans ce contexte industriel, les approches décentralisées sans et avec découplage sont envisagées. La stratégie décentralisée pure met en œuvre un correcteur diagonal, ce qui revient à asservir un système par plusieurs boucles monovariables indépendantes. Bien que relativement facile à synthétiser et à implanter, la stratégie décentralisée ne permet pas d’atteindre les performances souhaitées en présence d’interactions importantes. Dans ce cas, il est possible de l’associer à des compensateurs permettant de diminuer les interactions.Une part importante de ces travaux de recherche concerne le développement méthodologique de ces stratégies. La définition d’une stratégie de commande est la première étape. Pour cela, la quantification du niveau d’interaction dans un système se révèle importante. Celle-ci peut être réalisée à l’aide de différentes méthodes et indicateurs qui s’appuient sur les réponses fréquentielles ou temporelles du système, ou encore sur les grammiens de commandabilité et d’observabilité. Une procédure systématique d’analyse des interactions a été proposée afin de déterminer la stratégie de commande la plus adaptée en fonction des interactions. Dans le cas où l’analyse des interactions conduit à adopter une stratégie décentralisée, les régulateurs peuvent être synthétisés à l’aide de méthodes monoboucles ou multiboucles. Les premières ne prennent pas en compte les interactions tandis que les secondes, plus élaborées mais également plus complexes à mettre en œuvre, permettent de les prendre spécifiquement en compte. A la suite de l’analyse de ces méthodes, une étude récapitulative présentant les méthodes préconisées en fonction du procédé et des objectifs, est finalement proposée. Dans le cas où l’analyse des interactions montre un niveau de couplage trop important, il est possible d’associer des compensateurs à la régulation décentralisée. Les compensateurs ont pour but de découpler les commandes vis-à-vis des sorties du procédé. Différentes méthodes et structures de découplage ont été étudiées et comparées. Une procédure de découplage, composée des méthodes considérées comme les plus efficaces a finalement été mise en place. / In this Ph.D. thesis, we explore the different steps of designing a decentralized control applied on a turboprop engine.From the control point of view, the turboprop engine is a TITO (Two-Input Two-Output) process. The fuel flow is used to control the shaft power while the blade pitch angle is used to control the propeller speed. The turboprop presents important couplings between manipulated variables and controlled variables. When the fuel flow changes, the propeller speed is impacted. Similarly, when controlling the blade pitch angle to change the propeller speed to another level, the shaft power is affected, particularly during the transient states. The main objective of this research thesis is to design control laws for the turboprop. Beside technical specifications like response time and overshoot, couplings between loops have to be reduced as much as possible and control laws have to be robust to model uncertainties. For this industrial environment a decentralized strategy (with or without compensators) has been chosen. The decentralized strategy consists in designing monoloop controllers in order to drive the multivariable system. The decentralized strategy presents important benefits, such as flexibility as well as design simplicity, but is not efficient in presence of heavy couplings. In that case, it is possible to use compensators that reduce existing process interactions before designing the monoloop controllers.An important part of this work focuses on the development of these different strategies.The first step is the choice of the control structure, which strongly depends on the level of interaction. Despite the availability of different metrics - based on frequential responses, temporal responses, or Gramian – it is not easy to know which one is the most appropriate. Based on the analysis of couplings with different metrics, a procedure is proposed in order to choose the structure and the controllers design method.If the coupling analysis leads to adopt a decentralized strategy, the controllers can be designed using monoloop or multiloop methods. The first ones are simple but do not take couplings into account, whereas multiloop methods take specifically couplings into account but are more complicated. These tuning methods have been studied and recommendations have finally been made to choose the most appropriated method depending on the process and the requirements.In cases where the couplings analysis reveals a high couplings level, compensators can be associated with the decentralized strategy. The objectives of the compensators are to reduce couplings in the system and to facilitate the design of monoloop controllers. Several decoupling structures have been studied and compared. A decoupling procedure has then been proposed.These methodological studies have been applied to the turboprop engine. Following the coupling analysis, a decentralized strategy with decoupling has been chosen. After following the decoupling procedure and trying different solutions, the inverted decoupler has been adopted. Considering the dynamics of the system and the total decoupling provided by the inverted decoupler, PI controllers have been used and a monoloop tuning method has been chosen. In order to guarantee the desired performances over the whole flight envelope, control laws have been interpolated, using a gain scheduling technique. The structured singular value approach has then been used to demonstrate the robustness of the control laws with model uncertainties. Control laws have finally been implemented in the control software and simulation results have illustrated their good performances.

Phosphate is an essential nutrient for all forms of life. Escherichia coli has a PhoR/PhoB two component regulatory system that controls the expression of various genes whose products allow the cell to thrive in low phosphate environments. The signaling mechanism of the PhoR/PhoB system has been studied and the phosphorylation cascade that controls gene expression is well understood. What is still unknown is how PhoR senses the phosphate level of the environment. The PstS, PstC, PstA, PstB, and PhoU proteins play a role in this signal sensing. This work confirms the hypothesis that the PstSCAB complex senses the environmental phosphate and that phosphate signal is passed through PhoU to PhoR. Further, this work characterizes residues important for interaction on PhoU and PhoR and identifies a structural model for interaction. This model points to a potential mechanism for PhoU mediated signaling to PhoR. We tested this model with direct coupling analysis and obtained further confirmation. Further use of these techniques may elucidate more of the interactions necessary for proper phosphate signaling.

Superóxido dismutases (SODs) são metaloenzimas que convertem o ânion superóxido em oxigênio molecular (O2) e peróxido de hidrogênio (H2O2). A presença de metal nessas enzimas está diretamente relacionada com seus mecanismos de catálise e com suas estruturas tridimensionais. Evolucionariamente, FeSOD e MnSOD podem ter evoluído de um gene ancestral comum, porque possuem sequências homólogas e estruturas cristalográficas sobreponíveis. Entretanto, a nível catalítico, ambas as proteínas divergiram o suficiente para que seus metais não possam ser intercambiáveis, produzindo uma enzima funcional, indicando que essas proteínas possuem alta especificidade por metal. O objetivo deste projeto de pesquisa é Identificar os determinantes estruturais do ajuste fino da especificidade por metal de MnSOD e FeSOD. Inicialmente, pretendese selecionar resíduos para mutagênese sítio-dirigida em TrMnSOD e TbFeSODB2, a partir de análise de acoplamento estatístico (SCA). Em seguida, mutantes serão construídos, expressos, purificados e cristalizados. A estrutura tridimensional dos mutantes será resolvida por cristalografia e sua atividade enzimática determinada, bem como a acomodação estrutural dos metais por Resonância Paramagnética Eletrônica. Nossa hipótese de trabalho é que através de SCA é possível elencar resíduos de aminoácidos candidatos para mutagênese sítio-dirigida para desenhar novas SODs, com características intermediárias de ligação por Fe/Mn, como possibilidade de interconversão de especificidade, caminhando na história evolutiva dessas moléculas. / Superoxide dismutases (SODs) are metalloenzymes that convert the superoxide anion in molecular oxygen (O2) and hydrogen peroxide (H2O2). The metal in the catalytic center of such enzymes is directly related to their catalysis mechanisms and tridimensional structures. Evolutionarily, FeSOD and MnSOD may have evolved from a common ancestor, because both proteins have homologous primary sequences and superposable crystallographic structures. However, at the catalytic level, both proteins diverged sufficiently to prevent interchange of their metallic centers, which would generate non-functional enzymes, indicating that these proteins have high metal specificity. The objective of this research project is to identify structural determinants of Fe/MnSODs necessary to metal specificity. We intend to use statistical coupling analysis (SCA) to select amino acid residues for site-directed mutagenesis in TrMnSOD e TbFeSODB2. Mutant genes will be constructed and their proteins expressed, purified and crystallized. The tridimensional structure of such mutants will be solved by X-ray crystallography and their enzymatic activities determined, as well as their electron paramagnetic resonance spectra. We hypothesize that SCA is useful to identify amino acid candidates for site-directed mutagenesis to design new SODs with intermediated Fe/Mn specificity, and even metal specificity interconversion, by studying the evolutionary history of these proteins.

A Análise de Acoplamentos Estatísticos é uma técnica computacional capaz de identificar resíduos importantes para a estrutura e função de proteínas em uma família por meio da quantificação de conservação posicional, correlação entre posições e identificação de grupos de resíduos correlacionados entre si. Neste trabalho, a análise de acoplamentos estatísticos foi implementada e aplicada ao estudo das proteínas tirosina fosfatases. Em conjunto com as proteínas tirosina quinases (PTKs), que adicionam um grupo fosforil a um resíduo de tirosina em uma proteína, as proteínas tirosina fosfatases (PTPs), que o removem, são responsáveis por diversos processos de sinalização celular. Elas são um caso de evolução convergente, onde um subgrupo (as proteínas tirosina fosfatases de baixo peso molecular) não apresenta homologia às chamadas PTPs \"clássicas\", capazes de defosforilar apenas resíduos de tirosina, e às fosfatases de especifidicade dupla, capazes de defosforilar também resíduos de serina e treonina, além de substratos não-protéicos. Em comum, as três subfamílias apresentam apenas o motivo CX5R, característico para todas as PTPs. Através do estudo das três subfamílias utilizando a análise de acoplamentos estatísticos, foi possível obter uma descrição detalhada de suas características conservadas e correlacionadas, relacionando-as ao conhecimento acumulado sobre proteínas tirosina fosfatases e a questões em aberto como a regulação por dimerização, a especificidade e mutações relacionadas a patologias. Foi possível também apresentar um método capaz de distinguir proteínas tirosina fosfatases de baixo peso molecular das arsenato redutases, derivadas das primeiras por evolução divergente. Adicionalmente, a técnica foi aplicada ao estudo das hexoquinases, às superóxido dismutases e às peroxidases. A tese descreve também estudos desenvolvidos pelo autor na área de cristalografia de proteínas a determinação das estruturas da Transtirretina humana em complexo com genisteína, da holo-Hexoquinase PI de S. cerevisae, do complexo IL-22/IL-22R1 e da Laminarinase de R. marinus. / The statistical coupling analysis is a computational technique which can identify important residues for the structure and function of proteins in a family by quantifying positional conservation, correlation between positions and identifying groups of self-correlating residues. Its implementation in this research group was applied to the study of the protein tyrosine phosphatases. Together with the protein tyrosine kinases (PTKs), which add a phosphoryl group to a tyrosine residue in proteins, the protein tyrosine phosphatases (PTPs), which remove it, are responsible for a variety of cell signaling processes. They are a case of convergent evolution, since one subgroup (the low molecular weight protein tyrosine phosphatases) are not homologous to the classical phosphatases, which can only dephosphorilate tyrosine residues, and the dual-specificity phosphatases, which can also dephosphorilate serine and threonine residues, and also non-proteinaceous substrates. All three sub-families have, in common, the CX5R motif, a characteristic of all PTPs. By applying the statistical coupling analysis to the study of the three sub-families, it was possible to obtain a detailed depiction of their conserved and correlated characteristics, relating them to the accumulated knowledge on protein tyrosine phosphatases and open questions such as protein regulation by dimerization, specificity and disease-related mutations. It was also possible to present a method to distinguish between low molecular weight phosphatases and arsenate reductases, which are derived by the former by divergent evolution. In addition, the technique was applied to the study of hexokinases, superoxide dismutases and peroxidases. The thesis also describe studies developed by the author in the field of protein crystallography the structure determination of human transthyretin in complex with genistein, holo-hexokinase PI from S. cerevisae, the IL-22/IL-22R1 complex and the laminarinase from R. marinus.

Die Untersuchung kausaler Zusammenhänge in komplexen dynamischen Systemen spielt in der Wissenschaft eine immer wichtigere Rolle. Ziel dieses aktuellen, interdisziplinären Forschungsbereiches ist ein grundlegendes, tiefes Verständnis der vorherrschenden Prozesse und deren Wechselwirkungen in solchen Systemen. Die Untersuchung von Zeitreihen mithilfe moderner Kopplungsanalysemethoden liefert dabei Möglichkeiten zur Modellierung der betreffenden Systeme und somit bessere Vorhersagemethoden und fortgeschrittene Interpretationsmöglichkeiten der Ergebnisse. In der vorliegenden Arbeit werden zunächst einige existierende Kopplungsmaße mit ihren jeweiligen Anwendungsgebieten vorgestellt. Eine Gemeinsamkeit dieser Maße liegt in der Voraussetzung stationärer Zeitreihen, um die Anwendbarkeit zu gewährleisten. Daher wird im Verlauf der Dissertation eine Möglichkeit zur Erweiterung solcher Maße vorgestellt, die eine Kopplungsanalyse mit einer sehr hohen Zeitauflösung und somit auch die Untersuchung nichtstationärer, transienter Ereignisse ermöglicht. Die Erweiterung basiert auf der Verwendung von Ensembles von Messreihen und der Schätzung der jeweiligen Maße über das Ensemble anstatt über die Zeit. Dies ermöglicht eine Zeitauflösung bei der Analyse in der Größenordnung der Abtastrate des ursprünglichen Signals, die nur von der Art der verwendeten Kopplungsmaße abhängt. Der Ensemble-Ansatz wird auf verschiedene Kopplungsmaße angewandt. Zunächst werden die Methoden ausführlich an verschiedenen theoretischen Modellen und unter verschiedenen Bedingungen getestet. Anschließend erfolgt eine zeitaufgelöste Kopplungsanalyse kardiovaskulärer Zeitreihen, die während transienter Ereignisse aufgenommen wurden. Die Ergebnisse dieser Analyse bestätigen zum einen aktuelle Studienresultate, liefern aber auch neue Erkenntnisse, die es in Zukunft ermöglichen können, Modelle des Herz-Kreislauf-Systems zu erweitern und zu verbessern. / The analysis of causal relationships in complex dynamic systems plays a more and more important role in various scientific fields. The aim of this current, interdisciplinary field of research is a fundamental, deep understanding of predominant processes and their interactions in such systems. The study of time series using modern coupling analysis tools allows the modelling of the respective systems and thus better prediction methods and advanced interpretation possibilities for the results. In this work, initially some existing coupling measures and their fields of application are introduced. One trait these measures have in common is the requirement of stationary time series to ensure their applicability. Therefore, in the course of this thesis a possibility to extend these measures is presented, which allows a coupling analysis with a high temporal resolution and thus also the analysis of transient, nonstationary events. The extension is based on the use of ensembles of time series and the calculation of the respective measures across these ensembles instead of across time. This allows for a temporal resolution of the same order of magnitude as the sampling rate in the original signal. The resolution only depends on the kind of coupling analysis method employed. The ensemble extension is applied to different coupling measures. To begin with, the regarded tools are tested on various theoretical models and under different conditions. This is followed by a coupling analysis of cardiovascular time series recorded during transient events. The results on the one hand confirm topical study outcomes and on the other hand deliver new insights, which will allow to extend and improve cardiovascular system models in the future.

A Análise de Acoplamentos Estatísticos é uma técnica computacional capaz de identificar resíduos importantes para a estrutura e função de proteínas em uma família por meio da quantificação de conservação posicional, correlação entre posições e identificação de grupos de resíduos correlacionados entre si. Neste trabalho, a análise de acoplamentos estatísticos foi implementada e aplicada ao estudo das proteínas tirosina fosfatases. Em conjunto com as proteínas tirosina quinases (PTKs), que adicionam um grupo fosforil a um resíduo de tirosina em uma proteína, as proteínas tirosina fosfatases (PTPs), que o removem, são responsáveis por diversos processos de sinalização celular. Elas são um caso de evolução convergente, onde um subgrupo (as proteínas tirosina fosfatases de baixo peso molecular) não apresenta homologia às chamadas PTPs \"clássicas\", capazes de defosforilar apenas resíduos de tirosina, e às fosfatases de especifidicade dupla, capazes de defosforilar também resíduos de serina e treonina, além de substratos não-protéicos. Em comum, as três subfamílias apresentam apenas o motivo CX5R, característico para todas as PTPs. Através do estudo das três subfamílias utilizando a análise de acoplamentos estatísticos, foi possível obter uma descrição detalhada de suas características conservadas e correlacionadas, relacionando-as ao conhecimento acumulado sobre proteínas tirosina fosfatases e a questões em aberto como a regulação por dimerização, a especificidade e mutações relacionadas a patologias. Foi possível também apresentar um método capaz de distinguir proteínas tirosina fosfatases de baixo peso molecular das arsenato redutases, derivadas das primeiras por evolução divergente. Adicionalmente, a técnica foi aplicada ao estudo das hexoquinases, às superóxido dismutases e às peroxidases. A tese descreve também estudos desenvolvidos pelo autor na área de cristalografia de proteínas a determinação das estruturas da Transtirretina humana em complexo com genisteína, da holo-Hexoquinase PI de S. cerevisae, do complexo IL-22/IL-22R1 e da Laminarinase de R. marinus. / The statistical coupling analysis is a computational technique which can identify important residues for the structure and function of proteins in a family by quantifying positional conservation, correlation between positions and identifying groups of self-correlating residues. Its implementation in this research group was applied to the study of the protein tyrosine phosphatases. Together with the protein tyrosine kinases (PTKs), which add a phosphoryl group to a tyrosine residue in proteins, the protein tyrosine phosphatases (PTPs), which remove it, are responsible for a variety of cell signaling processes. They are a case of convergent evolution, since one subgroup (the low molecular weight protein tyrosine phosphatases) are not homologous to the classical phosphatases, which can only dephosphorilate tyrosine residues, and the dual-specificity phosphatases, which can also dephosphorilate serine and threonine residues, and also non-proteinaceous substrates. All three sub-families have, in common, the CX5R motif, a characteristic of all PTPs. By applying the statistical coupling analysis to the study of the three sub-families, it was possible to obtain a detailed depiction of their conserved and correlated characteristics, relating them to the accumulated knowledge on protein tyrosine phosphatases and open questions such as protein regulation by dimerization, specificity and disease-related mutations. It was also possible to present a method to distinguish between low molecular weight phosphatases and arsenate reductases, which are derived by the former by divergent evolution. In addition, the technique was applied to the study of hexokinases, superoxide dismutases and peroxidases. The thesis also describe studies developed by the author in the field of protein crystallography the structure determination of human transthyretin in complex with genistein, holo-hexokinase PI from S. cerevisae, the IL-22/IL-22R1 complex and the laminarinase from R. marinus.