Proteine spielen auf der zellulären Ebene eines Organismus eine fundamentale Rolle. Sie sind quasi die „Maschinen“ der Zelle. Ihre Bedeutung wird nicht zuletzt in ihrem Namen deutlich, welcher 1838 erstmals von J. Berzelius verwendet wurde und „das Erste“, „das Wichtigste“ bedeutet. Proteine sind aus Aminosäuren aufgebaute Moleküle. Unter physiologischen Bedingungen besitzen sie eine definierte dreidimensionale Gestalt, welche für ihre biologische Funktion bestimmend ist. Es wird heutzutage davon ausgegangen, dass diese dreidimensionale, stabile Struktur von Proteinen eindeutig durch die Abfolge der einzelnen Aminosäuren, der Sequenz, bestimmt ist. Diese Abfolge ist für jedes Protein in der Desoxyribonukleinsäure (DNS) gespeichert. Es ist allerdings eines der größten ungelösten Probleme der letzten Jahrzehnte, wie die Beziehung zwischen Sequenz und 3D-Struktur tatsächlich aussieht. Die Beantwortung dieser Fragestellung erfordert interdisziplinäre Ansätze aus Biologie, Informatik und Physik. In dieser Arbeit werden mit Hilfe von Methoden der theoretischen (Bio-) Physik einige der damit verbundenen Aspekte untersucht. Das Hauptaugenmerk liegt dabei auf Wechselwirkungen der einzelnen Aminosäuren eines Proteins untereinander, wofür in dieser Arbeit ein entsprechendes Energiemodell entwickelt wurde. Es werden Grundzustände sowie Energielandschaften untersucht und mit experimentellen Daten verglichen. Die Stärke der Wechselwirkung einzelner Aminosäuren erlaubt zusätzlich Aussagen über die Stabilität von Proteinen bezüglich mechanischer Kräfte. Die vorliegende Arbeit unterteilt sich wie folgt: Kapitel 2 dient der Einleitung und stellt Proteine und ihre Funktionen dar. Kapitel 3 stellt die Modellierung der Proteinstrukturen in zwei verschiedenen Modellen vor, welche in dieser Arbeit entwickelt wurden, um 3D-Strukturen von Proteinen zu beschreiben. Anschließend wird in Kapitel 4 ein Algorithmus zum Auffinden des exakten Energieminimums dargestellt. Kapitel 5 beschäftigt sich mit der Frage, wie eine geeignete diskrete Energiefunktion aus experimentellen Daten gewonnen werden kann. In Kapitel 6 werden erste Ergebnisse dieses Modells dargestellt. Der Frage, ob der experimentell bestimmte Zustand dem energetischen Grundzustand eines Proteins entspricht, wird in Kapitel 7 nachgegangen. Die beiden Kapitel 8 und 9 zeigen die Anwendung des Modells an zwei Proteinen, dem Tryptophan cage protein als dem kleinsten, stabilen Protein und Kinesin, einem Motorprotein, für welches 2007 aufschlussreiche Experimente zur mechanischen Stabilität durchgeführt wurden. Kapitel 10 bis 12 widmen sich Membranproteinen. Dabei beschäftigt sich Kapitel 10 mit der Vorhersage von stabilen Bereichen (sog. Entfaltungsbarrieren) unter externer Krafteinwirkung. Zu Beginn wird eine kurze Einleitung zu Membranproteinen gegeben. Im folgenden Kapitel 11 wird die Entfaltung mit Hilfe des Modells und Monte-Carlo-Techniken simuliert. Mit dem an Membranproteine angepassten Wechselwirkungsmodell ist es möglich, den Einfluss von Mutationen auch ohne explizite strukturelle Informationen vorherzusagen. Dieses Thema wird in Kapitel 12 diskutiert. Die Beziehung zwischen Primär- und Tertiärstruktur eines Proteins wird in Kapitel 13 behandelt. Es wird ein Ansatz skizziert, welcher in der Lage ist, Strukturbeziehungen zwischen Proteinen zu detektieren, die mit herkömmlichen Methoden der Bioinformatik nicht gefunden werden können. Die letzten beiden Kapitel schließlich geben eine Zusammenfassung bzw. einen Ausblick auf künftige Entwicklungen und Anwendungen des Modells.

Biological molecules are essential parts of organisms and participate in a variety of biological processes within cells. Understanding the relationship between sequence, structure, and function of biological molecules are of fundamental importance in life science and the health care industry. In this dissertation, a multi-scale approach was utilized to develop coarse-grained molecular models for protein and RNA simulations. By simplifying the atomistic representation of a biomolecular system, the coarse-grained approach enables the molecular dynamics simulations to reveal the biological processes, which occur on the time and length scales that are inaccessible to the all-atom models. For RNA, an "intermediate" coarse-grained model was proposed to provide both accuracy and efficiency for RNA 3D structure modeling and prediction. The overall potential parameters were derived based on structural statistics sampled from experimental structures. For protein, a general, transferable coarse-grain framework based on the Gay-Berne potential and electrostatic point multipole expansion was developed for polypeptide simulations. Next, an advanced atomistic model was developed to model electrostatic interaction with high resolution and incorporates electronic polarization effect that is ignored in conventional atomistic models. The last part of my thesis work involves applying all-atom molecular simulations to address important questions and problems in biophysics and structural biology. For example, the interaction between protein and miRNA, the recognition mechanism of antigen and antibody, and the structure dynamics of protein in mixed denaturants. / text

Polymer Nanocomposites (PNC) are a new class of materials characterized by their large interfacial areas between the host polymer and nanofiller. This unique feature, due to the size of the nanofiller, is understood to be the cause of enhanced mechanical, electrical, optical, and barrier properties observed of PNCs, relative to the properties of the unfilled polymer. This interface can determine the miscibility of the nanofiller in the polymer, which, in turn, influences the PNC's properties. In addition, this interface alters the polymer's structure near the surface of the nanofiller resulting in heterogeneity of local properties that can be expressed at the macroscopic level. Considering the polymer-nanoparticle interface significantly influences PNC properties, it is apparent that some atomistic level of detail is required to accurately predict the behavior of PNCs. Though an all-atom simulation of a PNC would be able to accomplish the latter, it is an impractical approach to pursue even with the most advanced computational resources currently available. In this contribution, we develop (1) an equilibrium coarse-graining method to predict nanoparticle dispersion in a polymer melt, (2) a dynamic coarse-graining method to predict rheological properties of polymer-nanoparticle melt mixtures, and (3) a numerical approach that includes interfacial layer effects and polymer rigidity when predicting barrier properties of PNCs. In addition to the above, we study how particle and polymer characteristics affect the interfacial layer thickness as well as how the polymer-nanoparticle interface may influence the entanglement network in a polymer melt. More specifically, we use a mean-field theory approach to discern how the concentration of a semiflexible polymer, its rigidity and the particle's size determine the interfacial layer thickness, and the scaling laws to describe this dependency. We also utilize molecular dynamics and simulation techniques on a model PNC to determine if the polymer-nanoparticle interaction can influence the entanglement network of a polymer melt. / text

Η διπλωματική εργασία ασχολείται με την ανάγκη για έναν προηγμένο μηχανισμό ασφάλειας που θα παρέχει προστασία πληροφοριών από τους μη εξουσιοδοτημένους χρήστες. Τα περισσότερα συστήματα σε εταιρικό και βιομηχανικό επίπεδο χρησιμοποιούν την απλή εξουσιοδότηση (simple authorization) ή all-or-nothing όπου έχουμε παραχώρηση πρόσβασης στους πόρους του συστήματος εάν ο χρήστης είναι εξουσιοδοτημένος ή εάν δεν είναι άρνηση πρόβλεψης χωρίς να έχει προβλεφθεί κάποια ενδιάμεση λύση. Στην περίπτωση του ελέγχου πρόσβασης για υπηρεσίες Ιστού (web services) –που είναι εφαρμογές που παρέχονται μέσω Διαδικτύου όπως φαίνεται και από το όνομά τους- δεν είναι ικανοποιητική η παραχώρηση πρόσβασης σε ολόκληρη την υπηρεσία Ιστού δηλαδή η πρόσβαση στο υψηλότερο επίπεδο (coarse-grained access control) αλλά απαιτείται και η πρόσβαση σε κάποια ή κάποιες από τις μεθόδους την υπηρεσίας Ιστού δηλαδή η διαβαθμισμένη πρόσβαση (fine-grained access control). Η πολιτική ελέγχου πρόσβασης που χρησιμοποιήσαμε είναι ο έλεγχος πρόσβασης βασισμένος σε ρόλους (Role-based Access Control) όπου οι χρήστες αποκτούν πρόσβαση στους προστατευόμενους πόρους (μια ολόκληρη υπηρεσία Ιστού ή μέθοδο) συνδεόμενοι με ρόλους με τις κατάλληλες άδειες πρόσβασης δηλαδή μόνο εξουσιοδοτημένοι χρήστες έχουν πρόσβαση στους προστατευόμενους πόρους. Τέλος υποθέσαμε μία βιομηχανική υποδομή που παρέχει σε πελάτες πρόσβαση μέσω ενός OPC XML-DA server όπου το OPC είναι ένα σύνολο από ανοικτά πρότυπα που παρέχουν δια-λειτουργικότητα (interoperability) και συνδεσιμότητα (connectivity) μεταξύ βιομηχανικού αυτοματισμού και επιχειρησιακών συστημάτων. / -

We present an approach based on Model-Driven Development ideas to create Software Product Lines(SPLs). In Model-Driven SPL approaches, the derivation of a product starts from a domain application model. This model is transformed through several stages reusing model transformation rules until a product is obtained. Transformations rules are selected according to variants included in configurations created by product designers. Configurations include variants from variation points, which are relevant characteristics representing the variability of a product line. Our approach (1) provides mechanisms to improve the expression of variability of Model-Driven SPLs by allowing designers to create fine-grained configurations of products, and (2) integrates a product derivation process which uses decision models and Aspect-Oriented Programming facilitating the reuse, adaptation and composition of model transformation rules. We introduce constraint models which make it possible for product line architects to capture the scope of product lines using the concepts of constraint, cardinality property and structural dependency property. To configure products, we create domain models and binding models, which are sets of bindings between model elements and variants and satisfy the constraint models. We define a decision model as a set of aspects. An aspect maintains information of what and when transformations rules that generate commonalities of products must be intercepted (joinpoints) and what transformation rules (advices) that generate variable structures must be executed instead. Our strategy maintains uncoupled variants from model transformation rules. This solves problems related to modularization, coupling, flexibility and maintainability of transformations rules because they are completely separated from variants; thus, they can evolve independently.

Nuclear magnetic resonance (NMR) spectroscopy was used to determine the structure of transmembrane (TM) segment IX of the Na+/H+ exchanger isoform 1 (NHE1) in dodecylphosphocholine micelles. Studying isolated TM segments in this fashion constitutes a well-established "divide and conquer" approach to the study of membrane proteins, which are often extremely difficult to produce, purify, and reconstitute in full-length polytopic form. A similar approach was combined with NMR spin relaxation experiments to determine the peptide backbone flexibility of NHE1 TM VII. The combined NMR structural and dynamics studies are consistent with an important role for TM segment flexibility in the function of NHE1, a protein involved in apoptosis and myocardial disease. The study of the rhomboid protease system is also described from two perspectives: 1) I attempted to produce several TM constructs of the substrate spitz or a related construct and the production and purification are described in detail; and 2) I present coarse-grained molecular dynamics simulation results for the E. coli rhomboid ecGlpG and a spitz TM construct. Spitz appears to preferentially associate with rhomboid near TMs 1 and 3 rather than the proposed substrate gate at TM 5. The two proteins primarily interact at the termini of helices rather than within the hydrocarbon core of the bilayer. Finally, I present a detailed analysis of coarse-grained molecular dynamics simulations of the fibroblast growth factor receptor 3 TM domain dimerization. Specifically, algorithms are described for analyzing critical features of wild-type and G380R mutant constructs. The G380R mutation is the cause of achondroplasia, the most common form of human dwarfism. The results suggest that the proximity of a residue to the dimer interface may impact the severity of the mutant phenotype. Strikingly, heterodimer and mutant homodimer constructs exhibit a secondary dimer interface which may explain the increased signaling activity previously reported for the G380R mutation--the helices may rotate with the introduction of G380R. The unifying theme of this work is the 'study of membrane proteins' using complementary techniques from structural biology and computational biochemistry.

Mechanisms for improving the execution efficiency of graph algorithms on Data-Parallel Architectures were proposed and identified. Execution of graph algorithms on GPGPU architectures, the prevalent data-parallel architectures was considered. Irregular and data dependent accesses in graph algorithms were found to cause significant idle cycles in GPGPU cores. A prefetching mechanism that reduced the amount of idle cycles by prefetching a data-dependent access pattern found in graph algorithms was proposed. Storing prefetches in unused spare registers in addition to storing them in the cache was shown to be more effective by the prefetching mechanism. The design of the cache hierarchy for graph algorithms was explored. First, an exclusive cache hierarchy was shown to be beneficial at the cost of increased traffic; a region based exclusive cache hierarchy was shown to be similar in performance to an exclusive cache hierarchy while reducing on-chip traffic. Second, bypassing cache blocks at both the level one and level two caches was shown to be beneficial. Third, the use of fine-grained memory accesses (or cache sub-blocking) was shown to be beneficial. The combination of cache bypassing and fine-grained memory accesses was shown to be more beneficial than applying the two mechanisms individually. Finally, the impact of different implementation strategies on algorithm performance was evaluated for the breadth first search algorithm using different input graphs and heuristics to identify the best performing implementation for a given input graph were also discussed.

Austenitic stainless steels are commonly used in nuclear reactors and have been considered as potential structural materials in fusion reactors due to their excellent corrosion resistance, good creep and fatigue resistance at elevated temperatures, but their relatively low yield strength and poor radiation tolerance hinder their applications in high dose radiation environments. High angle grain boundaries have long been postulated as sinks for radiation-induced defects, such as bubbles, voids, and dislocation loops. Here we provide experimental evidence that high angle grain boundaries can effectively remove radiation-induced defects. The equal channel angular pressing (ECAP) technique was used to produce ultrafine grained Fe-Cr-Ni alloy. Mechanical properties of the alloy were studied at elevated temperature by tensile tests and in situ neutron scattering measurements. Enhanced dynamic recovery process at elevated temperature due to dislocation climb lowers the strain hardening rate and ductility of ultrafine grained Fe-Cr-Ni alloy. Thermal stability of the ultrafine grained Fe-Cr-Ni alloy was examined by ex situ annealing and in situ heating within a transmission electron microscope. Abnormal grain growth at 827 K (600°C) is attributed to deformation-induced martensite, located at the triple junctions of grains. Helium ion irradiation studies on Fe-Cr-Ni alloy show that the density of He bubbles, dislocation loops, as well as irradiation hardening are reduced by grain refinement. In addition, we provide direct evidence, via in situ Kr ion irradiation within a transmission electron microscope, that high angle grain boundaries in nanocrystalline Ni can effectively absorb irradiation-induced dislocation loops and segments. The density and size of dislocation loops in irradiated nanocrystalline Ni were merely half of those in irradiated coarse grained Ni. The results imply that irradiation tolerance in bulk metals can be effectively enhanced by microstructure refinement.

The shear strength, elastic moduli and plastic strain characteristics of scaled-down ballast materials are investigated by use of the parallel gradation technique. Uniformly graded ballast materials chosen for the investigation are limestone, basalt and steel-slag. Steel-slag is a byproduct material of Eregli Iron and Steel Works, which is suitable to meet the durability test requirements as well as the electrical resistivity and the waste contaminants regulatory level. Conventional triaxial testing at a strain rate of 0.4 mm/min is used to obtain these characteristics for the scaled-down materials with a diameter of 100 mm specimen under a confining stress of 35 kPa, 70 kPa and 105 kPa / whereas that of only 35 kPa is used to characterize the accumulated plastic strain. The angle of internal friction, f, and the apparent cohesion, c, may be conservatively taken to be 42o and 35 kPa for all materials. The elastic moduli values for all materials may be predicted within an adequate estimate for the engineering purposes by using the power law parameters, K and n, determined for L-9.5 (D50 = 12.7 mm), the coarsest gradation tested for limestone. K with a reference pressure, pr = 1 kPa and n values for L-9.5, respectively, are 4365 and 0.636 for initial / 8511 and 0.419 for secant / 25704 and 0.430 for unloading-reloading elastic moduli. The unloading-reloading moduli increased, as the number of cycles increased. An increase in unloading-reloading modulus at N = 20 obtained was roughly 15% for scaled-down limestone / 10% for the basalt / and 5% for the steel-slag. The plastic strain after first cycle, &amp / #949 / 1, and the plastic strain coefficient, C can be represented as a function of mean particle size for each material type. For the limestone, basalt and steel-slag prototype size, D50 = 45 mm, &amp / #949 / 1 values of 0.59, 0.43 and 0.75 and C values of 0.54, 1.42 and 0.74 are predicted, respectively.

Title: Complex investigation of fine-grained polycrystals of Cu and CuZr alloy processed by equal channel angular pressing and high pressure torsion Author: RNDr.Ondřej Srba Department: Department of Physics of Materials, Faculty of Mathematics and Physics, Charles University Prague Supervisor: Doc. RNDr. Miloš Janeček, CSc. Abstract: In the thesis the microstructure development, mechanical, elastic and corrosion properties of deformed specimens of pure Cu and binary alloy CuZr processed by equal channel angular pressing (ECAP) are investigated. Several properties of pure Cu processed by ECAP are compared with properties of the same material processed by high pressure torsion (HPT). The microstructure development is characterized in detail by several experimental techniques (light and electron microscopy, electron back scatter diffraction, positron annihilation spectroscopy, etc.). The microstructure development in specimens processed by ECAP is characterized by the continuous fragmentation of the initial coarse grain structure and the formation of new grains having the sizes in the submicrocrystalline range (of 460 nm and 260 nm in Cu and CuZr alloy, respectively). During the deformation by ECAP the fraction of high-angle grain boundaries, the dislocation density and the concentration of vacancies are...