Single-molecule spectroscopy has provided a means to uncover pathways and heterogeneities that were previously hidden beneath the ensemble average. Such heterogeneity, however, is often obscured by the artifacts of experimental noise and the occurrence of undesired processes within the experimental medium. This has subsequently caused in the need for new analytical methodologies. It is particularly important that objectivity be maintained in the development of new analytical methodology so that bias is not introduced and the results improperly characterized. The research presented herein identifies two such sources of experimental uncertainty, and constructs objective approaches to reduce their effects in the experimental results. The first, photoblinking, arises from the occupation of dark electronic states within the probe molecule, resulting in experimental data that is distorted by its contribution. A method based in Bayesian inference is developed, and is found to nearly eliminate photoblinks from the experimental data while minimally affecting the remaining data and maintaining objectivity. The second source of uncertainty is electronic shot-noise, which arises as a result of Poissonian photon collection. A method based in wavelet decomposition is constructed and applied to simulated and experimental data. It is iii found that, while making only one assumption, that photon collection is indeed a Poisson process, up to 75% of the shot-noise contribution may be removed from the experimental signal by the wavelet-based procedure. Lastly, in an effort to connect model-based approaches such as molecular dynamics simulation to model-free approaches that rely solely on the experimental data, a coarse-grained molecular model of a molecular ionic fluorophore diffusing within an electrostatically charged polymer brush is constructed and characterized. It is found that, while the characteristics of the coarse-grained simulation compare well with atomistic simulations, the model is lacking in its representation of the electrostatically-driven behavior of the experimental system.

The coarse-grained configurational-bias Monte Carlo (CG-CBMC) simulation was employed to study the structural behaviors of methyl methacrylate (MMA) oligomers adsorbed on grooved substrate due to molecular dynamics (MD) simulation is probably trapped at some local energy minima and difficult to carry out over a long enough time to allow relaxation of chain motion for an enormous polymeric system. Therefore, the CG-CBMC simulation was adopted in the present study. In this study, three types of chains are classified according to their positions relative to the groove. Type 1, Type 2, and Type 3 represent the entire MMA-oligomer within the groove, the MMA-oligomer partially within the groove, and the oligomer outside the groove, respectively. The orientational order parameters of Type 1 and Type 2 oligomers decrease with the increase of groove width, but the orientational order parameter of Type 3 oligomers is approximately equal to 0.1. In addition, observation of the orientational order parameters of Type 1 oligomers interacting with the grooved substrate at different interaction strengths decrease with increasing the groove width. Furthermore, the orientational order parameters of Type 1 oligomers within the narrowest (20 Å) and the widest (35 Å) groove with different depths were determined. For the narrowest groove, the arrangement of Type 1 oligomers will be influenced by the groove width. However, in the case of the widest groove, the orientational order parameter of Type 1 oligomers is approximately equal to 0.2. This study can help engineers clarify the characteristics and phenomena of physical adsorption of the molecules, as well as contributing to the application of recent technology.

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

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.

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.

abstract: Coarse-grained Reconfigurable Arrays (CGRAs) are promising accelerators capable of accelerating even non-parallel loops and loops with low trip-counts. One challenge in compiling for CGRAs is to manage both recurring and nonrecurring variables in the register file (RF) of the CGRA. Although prior works have managed recurring variables via rotating RF, they access the nonrecurring variables through either a global RF or from a constant memory. The former does not scale well, and the latter degrades the mapping quality. This work proposes a hardware-software codesign approach in order to manage all the variables in a local nonrotating RF. Hardware provides modulo addition based indexing mechanism to enable correct addressing of recurring variables in a nonrotating RF. The compiler determines the number of registers required for each recurring variable and configures the boundary between the registers used for recurring and nonrecurring variables. The compiler also pre-loads the read-only variables and constants into the local registers in the prologue of the schedule. Synthesis and place-and-route results of the previous and the proposed RF design show that proposed solution achieves 17% better cycle time. Experiments of mapping several important and performance-critical loops collected from MiBench show proposed approach improves performance (through better mapping) by 18%, compared to using constant memory. / Dissertation/Thesis / Masters Thesis Computer Science 2016

Dans cette thèse, nous nous sommes intéressés à la relation subtile qui existe entre lesstructures complexes des protéines et leurs fonctions encore plus raffinées que ces dernièreseffectuent. Basés sur deux descriptions différentes des protéines, à l’échelle de acide-aminé età l’echelle atomique, un de nos objectifs était de connecter des indicateurs structuraux calculésà partir de la topologie des protéines à des sites fonctionnels tels que les sites catalyiquesdans les enzymes. Un autre pan de la recherche de cette thèse était d’utiliser nos outils baséssur la structure et de mettre au point de nouvelles simulations numériques pour étudier lesdéterminants basiques structuraux et dynamiques de la communication intramoléculaire dansles protéines. Une première découverte fut de montrer comment l’analyse des modes normauxet la théorie des reseaux complexes conduisent à la prédiction des sites catalytiques dans lesenzymes. De plus, nous avons travaillé sur un groupe relativement peu connu de modes nor-maux qui ont la particularité d’être localisés à deux endroits très eloignés dans la structure desprotéines. Ces modes bilocalisés ont permis de réaliser des transferts d’énergie à des distancesconsidérables (plus de 70 Å). Finalement, des expériences de refroidissement effectuées sur unsystème protéine-eau décrit à l’échelle atomique ont dévoilé que le refroidissement induit unelocalisation spontanée d’énergie, indiquant certaines déformations des anneaux du benzenecomme possible centres de stockage de l’énergie dans les protéines. / In this thesis we have focused on the elusive relation that exists in proteins between theircomplex structures and the even more complex and sophisticated functions that they perform.Based on two different descriptions of proteins, at residue and atomistic scale, one of ouraims was to connect structural indicators computed from the topology of protein scaffoldsto hot spots in proteins such as catalytic sites in enzymes. Another goal of this thesis wasto employ our structure-based tools and set up original simulation scheme to investigate thebasic structural and dynamical determinants of intramolecular communication in proteins.As a first important finding, we have shown how normal mode analysis and specific graph-theoretical approaches lead to the prediction of catalytic sites in enzymes. Moreover, wehave concentrated our attention on an overlooked class of normal modes, that are stronglylocalized at two widely separated locations in protein scaffolds. These bilocalized modesturned out to efficiently mediate energy transfer even across considerable distances (morethan 70 Å). Finally, cooling experiments performed on a protein-water system described atatomic level have unveiled complex cooling-induced spontaneous energy localization patterns,pointing to specific deformation modes of benzene rings as potential energy-storage centers.

Sublevel caving (SLC) is a mass mining method relying on the flowability of the blasted material. The ore is blasted in slices against caved material which is mainly waste rock. The result of the confined blast is greatly influenced by the interaction between the blasted material and the caved material. During blasting both materials change characteristics; the blasted material increases its porosity and compressibility due to breakage and swelling while the caved material is compacted and decreases in porosity and compressibility. The understanding of the mechanisms involved in this process is of significant importance. The behavior of the caved material (confining material) was studied in laboratory under dynamic loading. A new apparatus was developed to conduct impact tests to simulate blasting conditions. The tested material was a blend of crushed waste rock from drift development in the Kiirunavaara mine with maximum particle size 32 mm. The material was tested for two conditions, i.e. dry and wet (pendular state), and with different impact velocities (low (5 m/s), medium (8 m/s) and high (10-12 m/s)). During the impact tests, two types of measurements were taken; dynamic measurements based on the recordings from the installed accelerometers on the machine and static measurements pre- and post-impact. Additionally, the angle of repose, the impact duration, and the fragmentation was measured. In addition to the laboratory tests, small-scale blasting tests were carried out to investigate the burden behavior in confined conditions. The blasted specimen was a cuboid magnetic mortar block and the confining material was crushed concrete with maximum particle size 16 mm. The blocks were instrumented with custom-made incremental displacement sensor. After the analysis of the results from the above experimental work, two confined pillar tests (test #1 and test #2) were carried out at the Kiirunavaara mine. The preparation work for the pillar tests involved the development of instrumentation and installation techniques. The experimental configuration contained two blastholes and measurement holes in between the blastholes drilled from the neighboring drift. Test #1 mainly focused on the evaluation of the instrumentation and techniques while test #2 was focused on the interaction between the blasted burden and the confining material. The confining material in test #1 was a blend of ore and waste material from drift development at the Kiirunavaara mine. The characteristics of the material were unknown. Test #2 was split into two parts, the confining material in the first part was the same as in the laboratory impact tests and the second part of the pillar was confined by caved masses. The instrumentation was installed in the burden of the pillars and was equipped with accelerometers and displacement sensor. Additional instrumentation was also installed in the confining material. The burden in the small-scale blasting tests reached maximum velocity 29 m/s and maximum displacement 12.6 mm. In pillar tests, the burden movement was in the range of 0.9 to 1.1 m. In both pillar tests, burden erosion material was observed in the gap between the intact and the blasted burden. This material was finer compared to the blasted burden. The origin of this material was from the vicinity of the blastholes. The results of the laboratory tests showed that the wet material exhibited larger compaction zone than that of the dry material. The wet material showed apparent cohesion close to the impact surface of the tested material. A similar observation was made in test #2 where an agglomeration of the confining material, as a result of apparent cohesion, was observed on the surface of the blasted burden. The displacement data from the instrumentation in the burden and inside the confining material showed that the compaction zone follows an inverse exponential behavior. After the blast steeper angles of repose were measured indicating higher frictional forces between the particles. Moreover, the evidence of apparent cohesion and a larger angle of repose indicated the introduction of tensile strength in the material. The mass of the confining material was compressed elastically and plastically during the blast. After the blast, the material recovered its elastic deformation and pushed the blasted burden backward as observed in the small-scale blasting tests and the pillar tests. At this stage, the burden erosion material was compacted. Hence, there were 3 materials, i.e. burden erosion material, burden and confining material, which were compacted with different compaction rates. This condition promotes interlocking of the particles in the materials. If this behavior is correlated with a production SLC ring, then it indicates disturbances in flowability of the blasted material.