Développements et applications de méthodes computationnelles pour l'étude de l'agrégation des protéines amyloïdes

Les protéines sont au coeur de la vie. Ce sont d'incroyables nanomachines moléculaires spécialisées et améliorées par des millions d'années d'évolution pour des fonctions bien définies dans la cellule. La structure des protéines, c'est-à-dire l'arrangement tridimensionnel de leurs atomes, est intimement liée à leurs fonctions. L'absence apparente de structure pour certaines protéines est aussi de plus en plus reconnue comme étant tout aussi cruciale. Les protéines amyloïdes en sont un exemple marquant : elles adoptent un ensemble de structures variées difficilement observables expérimentalement qui sont associées à des maladies neurodégénératives. Cette thèse, dans un premier temps, porte sur l'étude structurelle des protéines amyloïdes bêta-amyloïde (Alzheimer) et huntingtine (Huntington) lors de leur processus de repliement et d'auto-assemblage. Les résultats obtenus permettent de décrire avec une résolution atomique les interactions des ensembles structurels de ces deux protéines. Concernant la protéine bêta-amyloïde (AB), nos résultats identifient des différences structurelles significatives entre trois de ses formes physiologiques durant ses premières étapes d'auto-assemblage en environnement aqueux. Nous avons ensuite comparé ces résultats avec ceux obtenus au cours des dernières années par d'autres groupes de recherche avec des protocoles expérimentaux et de simulations variés. Des tendances claires émergent de notre comparaison quant à l'influence de la forme physiologique de AB sur son ensemble structurel durant ses premières étapes d'auto-assemblage. L'identification des propriétés structurelles différentes rationalise l'origine de leurs propriétés d'agrégation distinctes. Par ailleurs, l'identification des propriétés structurelles communes offrent des cibles potentielles pour des agents thérapeutiques empêchant la formation des oligomères responsables de la neurotoxicité. Concernant la protéine huntingtine, nous avons élucidé l'ensemble structurel de sa région fonctionnelle située à son N-terminal en environnement aqueux et membranaire. En accord avec les données expérimentales disponibles, nos résultats sur son repliement en environnement aqueux révèlent les interactions dominantes ainsi que l'influence sur celles-ci des régions adjacentes à la région fonctionnelle. Nous avons aussi caractérisé la stabilité et la croissance de structures nanotubulaires qui sont des candidats potentiels aux chemins d'auto-assemblage de la région amyloïde de huntingtine. Par ailleurs, nous avons également élaboré, avec un groupe d'expérimentateurs, un modèle détaillé illustrant les principales interactions responsables du rôle d'ancre membranaire de la région N-terminal, qui sert à contrôler la localisation de huntingtine dans la cellule. Dans un deuxième temps, cette thèse porte sur le raffinement d'un modèle gros-grain (sOPEP) et sur le développement d'un nouveau modèle tout-atome (aaOPEP) qui sont tous deux basés sur le champ de force gros-grain OPEP, couramment utilisé pour l'étude du repliement des protéines et de l'agrégation des protéines amyloïdes. L'optimisation de ces modèles a été effectuée dans le but d'améliorer les prédictions de novo de la structure de peptides par la méthode PEP-FOLD. Par ailleurs, les modèles OPEP, sOPEP et aaOPEP ont été inclus dans un nouveau code de dynamique moléculaire très flexible afin de grandement simplifier leurs développements futurs.

Closure of the Monte Carlo dynamical equation in the spherical Sherrington-Kirkpatrick model

We study the analytical solution of the Monte Carlo dynamics in the spherical Sherrington-Kirkpatrick model using the technique of the generating function. Explicit solutions for one-time observables (like the energy) and two-time observables (like the correlation and response function) are obtained. We show that the crucial quantity which governs the dynamics is the acceptance rate. At zero temperature, an adiabatic approximation reveals that the relaxational behavior of the model corresponds to that of a single harmonic oscillator with an effective renormalized mass.

Fragile-glass behavior of a short-range p-spin model

We propose a short-range generalization of the p-spin interaction spin-glass model. The model is well suited to test the idea that an entropy collapse is at the bottom line of the dynamical singularity encountered in structural glasses. The model is studied in three dimensions through Monte Carlo simulations, which put in evidence fragile glass behavior with stretched exponential relaxation and super-Arrhenius behavior of the relaxation time. Our data are in favor of a Vogel-Fulcher behavior of the relaxation time, related to an entropy collapse at the Kauzmann temperature. We, however, encounter difficulties analogous to those found in experimental systems when extrapolating thermodynamical data at low temperatures. We study the spin-glass susceptibility, investigating the behavior of the correlation length in the system. We find that the increase of the relaxation time is accompanied by a very slow growth of the correlation length. We discuss the scaling properties of off-equilibrium dynamics in the glassy regime, finding qualitative agreement with the mean-field theory.

First principles LDA+U and GGA+U study of cerium oxides: Dependence on the effective U-parameter

The electronic structure and properties of cerium oxides (CeO2 and Ce2O3) have been studied in the framework of the LDA+U and GGA(PW91)+U implementations of density functional theory. The dependence of selected observables of these materials on the effective U parameter has been investigated in detail. The examined properties include lattice constants, bulk moduli, density of states, and formation energies of CeO2 and Ce2O3. For CeO2, the LDA+U results are in better agreement with experiment than the GGA+U results whereas for the computationally more demanding Ce2O3 both approaches give comparable accuracy. Furthermore, as expected, Ce2O3 is much more sensitive to the choice of the U value. Generally, the PW91 functional provides an optimal agreement with experiment at lower U energies than LDA does. In order to achieve a balanced description of both kinds of materials, and also of nonstoichiometric CeO2¿x phases, an appropriate choice of U is suggested for LDA+U and GGA+U schemes. Nevertheless, an optimum value appears to be property dependent, especially for Ce2O3. Optimum U values are found to be, in general, larger than values determined previously in a self-consistent way.

Delta(1232) isobar excitations and the ground state of nuclei

The influence of Delta isobar components on the ground-state properties of nuclear systems is investigated for nuclear matter as well as finite nuclei. Many-body wave functions, including isobar configurations and binding energies, are evaluated employing the framework of the coupled-cluster theory. It is demonstrated that the effect of isobar configurations depends in a rather sensitive way on the model used for the baryon-baryon interaction. As examples for realistic baryon-baryon interactions with explicit inclusion of isobar channels we use the local (V28) and nonlocal meson-exchange potentials (Bonn2000) but also a model recently developed by the Salamanca group, which is based on a quark picture. The differences obtained for the nuclear observables are related to the treatment of the interaction, the pi-exchange contributions in particular, at high momentum transfers.

Atomic parity nonconservation, neutron radii, and effective field theories of nuclei

Accurately calibrated effective field theories are used to compute atomic parity nonconserving (APNC) observables. Although accurately calibrated, these effective field theories predict a large spread in the neutron skin of heavy nuclei. Whereas the neutron skin is strongly correlated to numerous physical observables, in this contribution we focus on its impact on new physics through APNC observables. The addition of an isoscalar-isovector coupling constant to the effective Lagrangian generates a wide range of values for the neutron skin of heavy nuclei without compromising the success of the model in reproducing well-constrained nuclear observables. Earlier studies have suggested that the use of isotopic ratios of APNC observables may eliminate their sensitivity to atomic structure. This leaves nuclear structure uncertainties as the main impediment for identifying physics beyond the standard model. We establish that uncertainties in the neutron skin of heavy nuclei are at present too large to measure isotopic ratios to better than the 0.1% accuracy required to test the standard model. However, we argue that such uncertainties will be significantly reduced by the upcoming measurement of the neutron radius in 208^Pb at the Jefferson Laboratory.

Correlations in hot asymmetric nuclear matter

Bulk and single-particle properties of hot hyperonic matter are studied within the Brueckner-Hartree-Fock approximation extended to finite temperature. The bare interaction in the nucleon sector is the Argonne V18 potential supplemented with an effective three-body force to reproduce the saturating properties of nuclear matter. The modern Nijmegen NSC97e potential is employed for the hyperon-nucleon and hyperon-hyperon interactions. The effect of temperature on the in-medium effective interaction is found to be, in general, very small and the single-particle potentials differ by at most 25% for temperatures in the range from 0 to 60 MeV. The bulk properties of infinite matter of baryons, either nuclear isospin symmetric or a Beta-stable composition that includes a nonzero fraction of hyperons, are obtained. It is found that the presence of hyperons can modify the thermodynamical properties of the system in a non-negligible way.

Bulk and single-particle properties of hyperonic matter at finite temperature

Bulk and single-particle properties of hot hyperonic matter are studied within the Brueckner-Hartree-Fock approximation extended to finite temperature. The bare interaction in the nucleon sector is the Argonne V18 potential supplemented with an effective three-body force to reproduce the saturating properties of nuclear matter. The modern Nijmegen NSC97e potential is employed for the hyperon-nucleon and hyperon-hyperon interactions. The effect of temperature on the in-medium effective interaction is found to be, in general, very small and the single-particle potentials differ by at most 25% for temperatures in the range from 0 to 60 MeV. The bulk properties of infinite matter of baryons, either nuclear isospin symmetric or a Beta-stable composition that includes a nonzero fraction of hyperons, are obtained. It is found that the presence of hyperons can modify the thermodynamical properties of the system in a non-negligible way.

Entropy of a correlated system of nucleons

Realistic nucleon-nucleon interactions induce correlations to the nuclear many-body system, which lead to a fragmentation of the single-particle strength over a wide range of energies and momenta. We address the question of how this fragmentation affects the thermodynamical properties of nuclear matter. In particular, we show that the entropy can be computed with the help of a spectral function, which can be evaluated in terms of the self-energy obtained in the self-consistent Green's function approach. Results for the density and temperature dependences of the entropy per particle for symmetric nuclear matter are presented and compared to the results of lowest order finite-temperature Brueckner-Hartree-Fock calculations. The effects of correlations on the calculated entropy are small, if the appropriate quasiparticle approximation is used. The results demonstrate the thermodynamical consistency of the self-consistent T-matrix approximation for the evaluation of the Green's functions.

Protein Folding Simulations: Confinement, External Fields and Sequence Design

The present Thesis looks at the problem of protein folding using Monte Carlo and Langevin simulations, three topics in protein folding have been studied: 1) the effect of confining potential barriers, 2) the effect of a static external field and 3) the design of amino acid sequences which fold in a short time and which have a stable native state (global minimum). Regarding the first topic, we studied the confinement of a small protein of 16 amino acids known as 1NJ0 (PDB code) which has a beta-sheet structure as a native state. The confinement of proteins occurs frequently in the cell environment. Some molecules called Chaperones, present in the cytoplasm, capture the unfolded proteins in their interior and avoid the formation of aggregates and misfolded proteins. This mechanism of confinement mediated by Chaperones is not yet well understood. In the present work we considered two kinds of potential barriers which try to mimic the confinement induced by a Chaperon molecule. The first kind of potential was a purely repulsive barrier whose only effect is to create a cavity where the protein folds up correctly. The second kind of potential was a barrier which includes both attractive and repulsive effects. We performed Wang-Landau simulations to calculate the thermodynamical properties of 1NJ0. From the free energy landscape plot we found that 1NJ0 has two intermediate states in the bulk (without confinement) which are clearly separated from the native and the unfolded states. For the case of the purely repulsive barrier we found that the intermediate states get closer to each other in the free energy landscape plot and eventually they collapse into a single intermediate state. The unfolded state is more compact, compared to that in the bulk, as the size of the barrier decreases. For an attractive barrier modifications of the states (native, unfolded and intermediates) are observed depending on the degree of attraction between the protein and the walls of the barrier. The strength of the attraction is measured by the parameter $\epsilon$. A purely repulsive barrier is obtained for $\epsilon=0$ and a purely attractive barrier for $\epsilon=1$. The states are changed slightly for magnitudes of the attraction up to $\epsilon=0.4$. The disappearance of the intermediate states of 1NJ0 is already observed for $\epsilon =0.6$. A very high attractive barrier ($\epsilon \sim 1.0$) produces a completely denatured state. In the second topic of this Thesis we dealt with the interaction of a protein with an external electric field. We demonstrated by means of computer simulations, specifically by using the Wang-Landau algorithm, that the folded, unfolded, and intermediate states can be modified by means of a field. We have found that an external field can induce several modifications in the thermodynamics of these states: for relatively low magnitudes of the field ($<2.06 \times 10^8$ V/m) no major changes in the states are observed. However, for higher magnitudes than ($6.19 \times 10^8$ V/m) one observes the appearance of a new native state which exhibits a helix-like structure. In contrast, the original native state is a $\beta$-sheet structure. In the new native state all the dipoles in the backbone structure are aligned parallel to the field. The design of amino acid sequences constitutes the third topic of the present work. We have tested the Rate of Convergence criterion proposed by D. Gridnev and M. Garcia ({\it work unpublished}). We applied it to the study of off-lattice models. The Rate of Convergence criterion is used to decide if a certain sequence will fold up correctly within a relatively short time. Before the present work, the common way to decide if a certain sequence was a good/bad folder was by performing the whole dynamics until the sequence got its native state (if it existed), or by studying the curvature of the potential energy surface. There are some difficulties in the last two approaches. In the first approach, performing the complete dynamics for hundreds of sequences is a rather challenging task because of the CPU time needed. In the second approach, calculating the curvature of the potential energy surface is possible only for very smooth surfaces. The Rate of Convergence criterion seems to avoid the previous difficulties. With this criterion one does not need to perform the complete dynamics to find the good and bad sequences. Also, the criterion does not depend on the kind of force field used and therefore it can be used even for very rugged energy surfaces.

Sociedad y educaci??n en Zaragoza durante la Restauraci??n (1874-1902)

Contribuir al mejor conocimiento de la responsabilidad de las Instituciones locales en un servicio tan importante como era el de la Instrucci??n P??blica. Interpretar los cambios que se produjeron en el ??mbito de la Instrucci??n Primaria y valorar si ??stos respondieron a unas expectativas y a unas necesidades sociales de esta ciudad en concreto. Presentar una panor??mica de la Instrucci??n Primaria a comienzos del siglo XX. Valorar el grado de eficiencia de las Instituciones. Detectar la preocupaci??n social existente por los aspectos educativos. La obra educativa realizada en la Restauraci??n en Zaragoza: aspectos comunes y diferencias con el resto del pa??s. Se analizan los siguientes aspectos: la sociedad zaragozana de la Restauraci??n; las Instituciones de promoci??n y control educativo; la pol??tica escolar municipal, las escuelas municipales, la infraestructura de las escuelas, el censo de alumnos, la situaci??n del profesorado; aspectos relacionados con la ense??anza (curr??culum y programas escolares, sistemas de ense??anza, m??todos de ense??anza, ex??menes p??blicos, material did??ctico); los centros privados; analfabetismo y proceso escolar; la Escuela Normal de Maestros y la Escuela Normal de Maestras; la educaci??n popular de adultos y la educaci??n popular de la mujer. Fuentes primarias. Documentos oficiales. Prensa local y profesional. Planos. Interpretaci??n y valoraci??n de los cambios producidos y comparaci??n con los del resto del pa??s. La situaci??n general de la Primera Ense??anza, al finalizar 1902, era muy diferente de la inicial. Los cambios m??s f??cilmente observables afectaban al n??mero de escuelas, al n??mero de alumnos escolarizados y al aumento de las consignaciones presupuestarias. La calidad de la ense??anza no sigui?? un ritmo paralelo al aumento cuantitativo, caracteriz??ndose por una deficiente infraestructura, frecuentes cambios en la localizaci??n, escasa dotaci??n para material escolar, persistencia de un profesorado auxiliar mal seleccionado y mal pagado. Frente a una Instrucci??n Primaria municipal que se considera escasa en sus objetivos, en los medios y posiblemente en los resultados, se desarrolla una ense??anza privada pujante, especialmente la de algunas ??rdenes religiosas, muchas de las cuales abrieron centros que se han mantenido hasta la actualidad. Respecto a las Escuelas Normales, se ha apreciado que muchas participaron de la situaci??n de abandono generalizado. La Corporaci??n Municipal asumi?? definitivamente la funci??n que le correspond??a respecto a la Instrucci??n Primaria en el nivel de edad propiamente escolar aunque no lleg?? a contar con el inter??s y, sobre todo, con la dotaci??n econ??mica que exig??a una mejora cualitativa de dicha ense??anza.

El bilingüismo hispanofrancés de los niños españoles escolarizados en Francia.

Demostrar que el habla bilingüe presenta unas características típicas y originales. Diferenciables de las propias del habla estandar monolingüe y que estas características, son observables en el discurso colectivo espontáneo. 240 redacciones de 180 alumnos divididos en dos grupos: A) experimental, dos subgrupos de alumnos bilingües, de habla francesa y española seleccionados en cuatro clases españolas complementarias. B) Grupo de contraste, dos subgrupos de alumnos monolingües, de habla francesa o española. La muestra es elegida al azar y es representativa. Se miden las siguientes variables: producciones y frecuencias del conjunto de vocablos en un texto tanto individuales como colectivas. Vocablos que aparecen una sola vez, éstos en contraposición con el total de vocablos. Comparación en los diferentes textos de: estructura y contenido léxico, organización sintáctica, contenido semántico, etc. Tipos de errores de cada subgrupo, originalidad de los mismos en los textos de los bilingües, en relación con los monolingües. Con las redacciones recogidas se constituye un cuerpo de producciones espontáneas de la muestra bilingüe, que se contrasta con las producciones de las muestras monolingües. Frecuencias de vocablos en la producción individual de cada sujeto. Léxico de cada subgrupo, frecuencia y dispersión de cada vocablo. Frecuencia total en cada subgrupo de las distintas categorías gramaticales de estudio. Comparación de los diferentes textos e interpretación lingüística de las diferencias observadas en función de las hipótesis. Acumulación de frecuencias en los vocablos más generales, frecuentes y polivalentes de cada lengua. Incorporación a cada una de sus lenguas del exceso relativo de determinados paradigmas funcionales característicos de una u otra. Preferencia por una fraseología simplificada: enumeraciones, yuxtaposiciones, coordinaciones, etc. Especialización de cada lengua en una temática característica. Aparecen nuevos tipos de errores desconocidos en los monolingües, como resultado de las interferencias entre ambos sistemas lingüisticos. Las actuaciones del grupo bilingüe responden a un modelo específico de competencia sensiblemente diferente del monolingüe. Con los sujetos bilingües ha de utilizarse una pedagogía de la diferenciación entre todos los planos del sistema lingüístico: léxico, gráfico, sintáctico para que se aprecien claramente las diferencias de ambas lenguas. Esta tarea exige del profesor un conocimiento profundo de ambas lenguas.

Thermodynamics and log–contrast analysis in fluid geochemistry

There are two principal chemical concepts that are important for studying the natural environment. The first one is thermodynamics, which describes whether a system is at equilibrium or can spontaneously change by chemical reactions. The second main concept is how fast chemical reactions (kinetics or rate of chemical change) take place whenever they start. In this work we examine a natural system in which both thermodynamics and kinetic factors are important in determining the abundance of NH+4 , NO−2 and NO−3 in superficial waters. Samples were collected in the Arno Basin (Tuscany, Italy), a system in which natural and antrophic effects both contribute to highly modify the chemical composition of water. Thermodynamical modelling based on the reduction-oxidation reactions involving the passage NH+4 -> NO−2 -> NO−3 in equilibrium conditions has allowed to determine the Eh redox potential values able to characterise the state of each sample and, consequently, of the fluid environment from which it was drawn. Just as pH expresses the concentration of H+ in solution, redox potential is used to express the tendency of an environment to receive or supply electrons. In this context, oxic environments, as those of river systems, are said to have a high redox potential because O2 is available as an electron acceptor. Principles of thermodynamics and chemical kinetics allow to obtain a model that often does not completely describe the reality of natural systems. Chemical reactions may indeed fail to achieve equilibrium because the products escape from the site of the rection or because reactions involving the trasformation are very slow, so that non-equilibrium conditions exist for long periods. Moreover, reaction rates can be sensitive to poorly understood catalytic effects or to surface effects, while variables as concentration (a large number of chemical species can coexist and interact concurrently), temperature and pressure can have large gradients in natural systems. By taking into account this, data of 91 water samples have been modelled by using statistical methodologies for compositional data. The application of log–contrast analysis has allowed to obtain statistical parameters to be correlated with the calculated Eh values. In this way, natural conditions in which chemical equilibrium is hypothesised, as well as underlying fast reactions, are compared with those described by a stochastic approach

Avaluació de les actituds cooperatives en els estudiants de magisteri

L’objectiu d’aquest treball és validar els criteris de Johnson i Johnson (1992) com a indicadors d’avaluació d’actituds cooperatives. Ens proposem definir, contrastar i avaluar noves eines d’actuació. Volem analitzar i valorar algunes de les interaccions, que es produeixen en el desenvolupament d’actituds cooperatives, assenyalant els punts forts i febles observats a través de l’observació directa i amb l’ajuda de l’enregistrament de vídeo, què ens permetrà copsar de manera contrastable les interaccions verbals i no verbals dels alumnes, aspecte que a través de l’observació directa no és possible. És la nostra intenció intentar donar resposta a diversos interrogants respecte el nostre objecte d’estudi, oferint elements de reflexió i cercant criteris per avaluar les actituds cooperatives, assenyalant quins són els trets que s’observen en major o en menor grau en relació amb Johnson i Johnson en els estudiants de magisteri. Per centrar els objectius de la recerca tindrem en compte una triple perspectiva: - La perspectiva del professorat - la perspectiva de l’alumnat - La perspectiva de les activitats Pretenem relacionar cada un dels criteris de Johnson i Johnson amb indicadors observables i poder fer valoracions respecte allò que són capaços de fer i en relació quan tenen dificultats. Com a avaluació d’aquesta contrastació volem recollir prioritàriament aquelles consideracions que ens ajudin a establir un bon plantejament dels resultats. Com a professors en la formació inicial de futurs mestres, creiem que és fonamental fomentar estratègies d’acció cooperatives per afavorir un procés d’ensenyament més creatiu, més sòlid i més enriquidor, en la mesura que el professorat i l’alumnat s’impliquin en la construcció i transmissió del coneixement. La nostra proposta es troba dins del plantejament del nou model d’educació superior que comporta el procés de Convergència Europea, en el qual el principal protagonista és l’estudiant. Amb el treball que presentem volem oferir un al·licient i un estímul per promoure noves metodologies participatives en el mon universitari que fomentin noves actituds i consolidin els valors democràtics. És la nostra intenció reflexionar sobre la realitat actual dels nostres estudiants que en un futur no gaire llunyà hauran de ser educadors referents i competents

El Parque Nacional de los Picos de Europa : naturaleza en el entorno de los Lagos de Covadonga

Resumen basado en la publicaci??n. Precede al t??tulo: itinerarios did??cticos