Primary Structure and Solution Conditions Determine Conformational Ensemble Properties of Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) are a class of proteins that do not exhibit well-defined three-dimensional structures. The absence of structure is intrinsic to their amino acid sequences, which are characterized by low hydrophobicity and high net charge per residue compared to folded proteins. Contradicting the classic structure-function paradigm, IDPs are capable of interacting with high specificity and affinity, often acquiring order in complex with protein and nucleic acid binding partners. This phenomenon is evident during cellular activities involving IDPs, which include transcriptional and translational regulation, cell cycle control, signal transduction, molecular assembly, and molecular recognition. Although approximately 30% of eukaryotic proteomes are intrinsically disordered, the nature of IDP conformational ensembles remains unclear. In this dissertation, we describe relationships connecting characteristics of IDP conformational ensembles to their primary structures and solution conditions. Using molecular simulations and fluorescence experiments on a set of base-rich IDPs, we find that net charge per residue segregates conformational ensembles along a globule-to-coil transition. Speculatively generalizing this result, we propose a phase diagram that predicts an IDP\u27s average size and shape based on sequence composition and use it to generate hypotheses for a broad set of intrinsically disordered regions (IDRs). Simulations reveal that acid-rich IDRs, unlike their oppositely charged base-rich counterparts, exhibit disordered globular ensembles despite intra-chain repulsive electrostatic interactions. This apparent asymmetry is sensitive to simulation parameters for representing alkali and halide salt ions, suggesting that solution conditions modulate IDP conformational ensembles. We refine the ion parameters using a calibration procedure that relies exclusively on crystal lattice properties. Simulations with these parameters recover swollen coil behavior for acid-rich IDRs, but also uncover a dependence on sequence patterning for polyampholytic IDPs. These contributions initiate an endeavor to elucidate general principles that enable prediction of an IDP\u27s conformational ensemble based on primary structure and solution conditions, a goal analogous to structure prediction for folded proteins. Such principles would provide a molecular basis for understanding the roles of IDPs in physiology and pathophysiology, guide development of agents that modulate their behavior, and enable their rational design from chosen specifications

Design of Nanoparticle-Based Carriers for Targeted Drug Delivery

Nanoparticles have shown promise as both drug delivery vehicles and direct antitumor systems, but they must be properly designed in order to maximize efficacy. Computational modeling is often used both to design new nanoparticles and to better understand existing ones. Modeled processes include the release of drugs at the tumor site and the physical interaction between the nanoparticle and cancer cells. In this paper, we provide an overview of three different targeted drug delivery methods (passive targeting, active targeting, and physical targeting) and compare methods of action, advantages, limitations, and the current stages of research. For the most commonly used nanoparticle carriers, fabrication methods are also reviewed. This is followed by a review of computational simulations and models on nanoparticle-based drug delivery

FPGA Accelerators on Heterogeneous Systems: An Approach Using High Level Synthesis

La evolución de las FPGAs como dispositivos para el procesamiento con alta eficiencia energética y baja latencia de control, comparada con dispositivos como las CPUs y las GPUs, las han hecho atractivas en el ámbito de la computación de alto rendimiento (HPC).A pesar de las inumerables ventajas de las FPGAs, su inclusión en HPC presenta varios retos. El primero, la complejidad que supone la programación de las FPGAs comparada con dispositivos como las CPUs y las GPUs. Segundo, el tiempo de desarrollo es alto debido al proceso de síntesis del hardware. Y tercero, trabajar con más arquitecturas en HPC requiere el manejo y la sintonización de los detalles de cada dispositivo, lo que añade complejidad.Esta tesis aborda estos 3 problemas en diferentes niveles con el objetivo de mejorar y facilitar la adopción de las FPGAs usando la síntesis de alto nivel(HLS) en sistemas HPC.En un nivel próximo al hardware, en esta tesis se desarrolla un modelo analítico para las aplicaciones limitadas en memoria, que es una situación común en aplicaciones de HPC. El modelo, desarrollado para kernels programados usando HLS, puede predecir el tiempo de ejecución con alta precisión y buena adaptabilidad ante cambios en la tecnología de la memoria, como las DDR4 y HBM2, y en las variaciones en la frecuencia del kernel. Esta solución puede aumentar potencialmente la productividad de las personas que programan, reduciendo el tiempo de desarrollo y optimización de las aplicaciones.Entender los detalles de bajo nivel puede ser complejo para las programadoras promedio, y el desempeño de las aplicaciones para FPGA aún requiere un alto nivel en las habilidades de programación. Por ello, nuestra segunda propuesta está enfocada en la extensión de las bibliotecas con una propuesta para cómputo en visión artificial que sea portable entre diferentes fabricantes de FPGAs. La biblioteca se ha diseñado basada en templates, lo que permite una biblioteca que da flexibilidad a la generación del hardware y oculta decisiones de diseño críticas como la comunicación entre nodos, el modelo de concurrencia, y la integración de las aplicaciones en el sistema heterogéneo para facilitar el desarrollo de grafos de visión artificial que pueden ser complejos.Finalmente, en el runtime del host del sistema heterogéneo, hemos integrado la FPGA para usarla de forma trasparente como un dispositivo acelerador para la co-ejecución en sistemas heterogéneos. Hemos hecho una serie propuestas de altonivel de abstracción que abarca los mecanismos de sincronización y políticas de balanceo en un sistema altamente heterogéneo compuesto por una CPU, una GPU y una FPGA. Se presentan los principales retos que han inspirado esta investigación y los beneficios de la inclusión de una FPGA en rendimiento y energía.En conclusión, esta tesis contribuye a la adopción de las FPGAs para entornos HPC, aportando soluciones que ayudan a reducir el tiempo de desarrollo y mejoran el desempeño y la eficiencia energética del sistema.---------------------------------------------The emergence of FPGAs in the High-Performance Computing domain is arising thanks to their promise of better energy efficiency and low control latency, compared with other devices such as CPUs or GPUs.Albeit these benefits, their complete inclusion into HPC systems still faces several challenges. First, FPGA complexity means its programming more difficult compared to devices such as CPU and GPU. Second, the development time is longer due to the required synthesis effort. And third, working with multiple devices increments the details that should be managed and increase hardware complexity.This thesis tackles these 3 problems at different stack levels to improve and to make easier the adoption of FPGAs using High-Level Synthesis on HPC systems. At a close to the hardware level, this thesis contributes with a new analytical model for memory-bound applications, an usual situation for HPC applications. The model for HLS kernels can anticipate application performance before place and route, reducing the design development time. Our results show a high precision and adaptable model for external memory technologies such as DDR4 and HBM2, and kernel frequency changes. This solution potentially increases productivity, reducing application development time.Understanding low-level implementation details is difficult for average programmers, and the development of FPGA applications still requires high proficiency program- ming skills. For this reason, the second proposal is focused on the extension of a computer vision library to be portable among two of the main FPGA vendors. The template-based library allows hardware flexibility and hides design decisions such as the communication among nodes, the concurrency programming model, and the application’s integration in the heterogeneous system, to develop complex vision graphs easily.Finally, we have transparently integrated the FPGA in a high level framework for co-execution with other devices. We propose a set of high level abstractions covering synchronization mechanism and load balancing policies in a highly heterogeneous system with CPU, GPU, and FPGA devices. We present the main challenges that inspired this research and the benefits of the FPGA use demonstrating performance and energy improvements.<br /

Multifunctional Hybrid Materials Based on Polymers: Design and Performance

Multifunctional hybrid materials based on polymers have already displayed excellent commitment in addressing and presenting solutions to existing demands in priority areas such as the environment, human health, and energy. These hybrid materials can lead to unique superior multifunction materials with a broad range of envisaged applications. However, their design, performance, and practical applications are still challenging. Thus, it is highly advantageous to provide a breakthrough in state-of-the-art manufacturing and scale-up technology to design and synthesize advanced multifunctional hybrid materials based on polymers with improved performance.The main objective of this interdisciplinary book is to bring together, at an international level, high-quality elegant collection of reviews and original research articles dealing with polymeric hybrid materials within different areas such as the following:- Biomaterials chemistry, physics, engineering, and processing;- Polymer chemistry, physics and engineering;- Organic chemistry;- Composites science;- Colloidal chemistry and physics;- Porous nanomaterials science;- Energy storage; and- Automotive and aerospace manufacturing

The Exploration of Small Molecules, Lanthanide Complexes, and Catalysis using Electronic Structure Theory, Dynamics, and Machine Learning

With the ever increasing availability of computational resources, more challenging chemical systems can be studied. Among these challenges are the rotational and vibrational spectra of diatomic molecules within spectroscopic accuracy, the environmental perturbations induced on a rotating water molecule, the prediction of free binding energies of lanthanide complexes using machine learning, and the study of catalytic mechanisms through a theoretical framework. High levels of electronic structure theory were combined with a rigorous treatment of either the anharmonic vibrational wave functions to study diatomic molecules or the rotational wave functions to study H2O-pH2 interactions. The former was initially applied to the CF+ cation and excellent agreement was observed between theoretical and experimental spectroscopic constants. Likewise, the H2O-pH2 interactions were utilized to identify satellite peaks in the infrared spectra of a H2O-doped, pH2 crystal lattice. These peaks most likely occur due to a vacancy site directly around the H2O molecule. The study of lanthanide complexes is challenging due to their unique electronic structure. Specifically, the study of lanthanide-tris-β-diketone complexes was studied to calculate their respective free binding energies. Machine learning was utilized in this instance to act as the function which mapped the structure of the β-diketone ligands to the free binding energies. Predictions were made and several β-diketone ligands were identified which maximized the separation between lanthanide and lutetium. Finally, the study of catalytic mechanisms using theoretical methods is not without challenge due to the complex electronic structure of such systems. The hydrogen evolution reaction, the dehalogenation of CH2Cl2, the hydrogenation of small, unsaturated hydrocarbons, and the hydroformylation reaction were studied using either molecular electrocatalysts or transmetalated forms of the HKUST-1 metal-organic framework

Characterization of Electronic and Ionic Transport in Soft and Hard Functional Materials

Control over concurrent transport of multiple carrier types is desired in both soft and hard materials. For both types of materials, I demonstrate ways to characterize and execute governance over both electronic and ionic transport, and apply these concepts in the fabrication of devices with applications in conducting composites, photovoltaics, electrochemical energy storage, and memristors. In soft materials, such as polymers, the topology of the binary polymer mesoscale morphology has major implications on the charge/ion transport. Traditional approaches to co-continuous structures involve either using blends of polymers or diblock copolymers. In polymer blends, the structures are kinetically trapped and thus have poor long term stability. In diblock polymers, such morphologies are not universally accessible to non-random coil polymers. I discuss an approach to binary polymer mesoscale morphologies via the assembly of polymer nanoparticles. In this strategy, polymers are assembled into spherical nanoparticles, which are then assembled into hierarchical mesoscale structures. First, I demonstrate, experimentally and computationally, that the electrical transport in semiconducting/insulating polymer nanoparticle assemblies can be predictably tuned according to power law percolation scaling. Then I show that nanoparticle assemblies can be utilized for tunable concurrent transport of electrons and holes for photovoltaics, and for electronic and ionic charges aimed at applications in electrochemical energy storage. For hard materials, I detail the characterization of mixed electronic and ionic transport in hybrid organic/inorganic lead triiodide perovskites. I used the understanding of mixed electronic and ionic transport in these materials to explain poorly understood phenomena such as photo-instability and current-voltage hysteresis. Then, I show several examples of interfacial materials, and the characterization and implications of their respective work functions, as charge transport materials to control selective charge extraction from perovskites. And finally, I show how interfacial charge transport materials with ionic functionality can be used to change the interfacial chemistry at perovskite/charge transport material interfaces to control both electronic and ionic transport. In this regard, I demonstrate how an adsorbing interface for mobile ions can be used to control current-voltage hysteresis and state-dependent resistance, introducing a novel paradigm of interfacial ion adsorption to fabricate novel perovskite-based memristor devices

ZIF-8 : novel catalytic material for the conversion of CO2 to cyclic carbonates.

The effective utilization of CO2 as a renewable raw material for the production of useful chemicals is an area of great interest. There are several motivations for producing chemicals from CO2 whenever possible: (1) CO2 is a cheap, non-toxic and nonflammable feedstock that can frequently replace toxic chemicals such as phosgene or isocyanates; (2) CO2 is a totally renewable feedstock compared to oil or coal; (3) the production of chemicals from CO2 can lead to totally new materials such as polymers; (4) new routes to existing chemical intermediates and products could be more efficient and economical than current methods; and (5) the production of chemicals from CO2 could have a small but significant positive impact on the global carbon balance. In particular, the catalytic conversion of CO2 into cyclic carbonates, which are useful chemical intermediates employed for the production of plastics and organic solvents, represents an attractive route for the efficient use of carbon dioxide. The development of superior performance catalysts requires novel materials with fundamentally different structural, compositional, adsorption and transport properties than those of conventional zeolites, metal oxides or metal phases which have been used in the past for CO2 conversion to carbonates. In this respect, metal organic frameworks have emerged as a novel type of crystalline porous materials, which combine highly desirable properties, such as uniform micropores, high surface areas, flexible chemistries, and exceptional thermal and chemical stability, making them ideal candidates for catalytic applications. Particularly, zeolitic imidazolate framework-8 (ZIF-8) is an appealing metal organic framework that could be used as catalyst for the conversion of CO2 into carbonates. The Lewis acid sites, associated with Zn2+ in ZIF-8 structure, are known to catalyze the coupling reaction of CO2 and epoxides. The basic sites in organic linker attract CO2 to be trapped in the structure. With the active catalytic site and promoted CO2 adsorption capacity, ZIF-8 could potentially be an effective catalyst for the conversion of CO2 to cyclic carbonates. The intellectual thrust of this proposal is the rational design of ZIF-8, which offers the possibility of demonstrating high catalytic performance for CO2 conversion to cyclic carbonates

Oxetanes: Recent Advances in Synthesis, Reactivity and Medicinal Chemistry

The 4-membered oxetane ring has been increasingly exploited for its behaviors, i.e. influence on physicochemical properties as a stable motif in medicinal chemistry, and propensity to undergo ring opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last 5 years up to the end of 2015. These methods are clustered by strategy for preparation of the ring (Sections 3 and 4), and further derivatisation of preformed oxetane-containing building blocks (Sections 5-7). Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally examples of oxetane derivatives in ring opening and ring expansion reactions are described

Trapping Elusive Cp*Co(III) Metallacycles: Implications in C-H Functionalization Processes

La conversió d'enllaços carboni–hidrogen en enllaços carboni–carboni o carboni–heteroàtom és una de les reaccions més atractives dins de la química orgànica. Entre les diferents estratègies desenvolupades al llarg de les últimes dècades, l'activació selectiva d'enllaços C–H, promoguda per metalls de transició, amb l'ajuda d'un grup director, s'ha convertit en una alternativa molt atractiva a les tradicionals reaccions d'acoblament creuat. El desenvolupament d'aquest camp ha estat dominat per l'ús de catalitzadors de metalls nobles. No obstant això, en els últims anys, catalitzadors de metalls més barats i abundants, com el cobalt, han esdevingut una alternativa molt interessant. En aquest context, l'ús de complexos de Cp*CoIII ha rebut especial atenció a causa de la seva capacitat per a promoure una gran varietat de reaccions de formació d'enllaços C–C i C–X. Malgrat els avanços realitzats, aquests sistemes encara estan en la seva infància en comparació amb els catalitzadors de Rh i Pd, a causa de la falta de coneixement fonamental. L'estudi sobre la naturalesa de les espècies reactives o el mecanisme implicat en aquestes transformacions s'ha vist obstaculitzat per la dificultat de detectar intermedis de reacció. Intrigats per aquesta problemàtica, en aquesta tesi doctoral hem explorat: i) el desenvolupament de noves estratègies per a accedir a aquests intermedis de reacció; ii) l'ús d'aquests metal·lacicles de Cp*CoIII, no sols per a obtenir informació del mecanisme sobre diferents reaccions catalitzades per aquests compostos, sinó també per a millorar la seva eficiència; i finalment, iii) l'estudi de l'efecte d'alguns additius en les etapes elementals involucrades en els cicles catalítics. El coneixement fonamental generat durant aquesta tesi doctoralLa conversión de enlaces carbono–hidrógeno en enlaces carbono–carbono o carbono–heteroátomo es una de las reacciones más atractivas dentro de la química orgánica. Entre las diferentes estrategias desarrolladas a lo largo de las últimas décadas, la activación selectiva de enlaces C–H, promovida por metales de transición, con la ayuda de un grupo director, se ha convertido en una alternativa muy atractiva a las tradicionales reacciones de acoplamiento cruzado. El desarrollo de este campo ha estado dominado por el empleo de catalizadores de metales nobles. Sin embargo, en los últimos años, catalizadores de metales más baratos y abundantes, como el cobalto, se han convertido en una alternativa muy interesante. Dentro de este contexto, el uso de complejos de Cp*CoIII ha recibido especial atención debido a su capacidad para promover a una gran variedad de reacciones de formación de enlaces C–C y C–X. A pesar de los avances realizados, estos sistemas aún están en su infancia en comparación con los catalizadores de Rh y Pd, debido a la falta de conocimiento fundamental. El estudio sobre la naturaleza de las especies reactivas o el mecanismo implicado en estas transformaciones se ha visto obstaculizado por la dificultad de detectar intermedios de reacción. Intrigados por esta problemática, en esta tesis doctoral hemos explorado: i) el desarrollo de nuevas estrategias para acceder a estos intermedios de reacción; ii) el uso de estos metalaciclos de Cp*CoIII, no sólo para obtener información mecanísitica sobre diferentes reacciones catalizadas por estos compuestos, sino también para mejorar su eficiencia; y finalmente, iii) el estudio del efecto de la adición de algunos aditivos en las etapas elementales involucradas en los ciclos catalíticos. El conocimiento fundamental generado durante esta tesis doctoral ha supuesto un gran avance en la catálisis de cobalto, especialmente a nivel molecular.The conversion of ubiquitous and typically inert C–H bonds into C–C and C–heteroatom bonds is one of the most attractive transformation in organic chemistry. Among the different strategies developed over the past decades, ligand-directed transition-metal-catalyzed transformations have achieved remarkable progress, becoming an attractive alternative to traditional cross-coupling reactions. During decades, these catalytic systems required noble transition metals for the efficient construction of organic molecules. However, in the past few years, more cost-effective first-row metals, such as cobalt, have emerged as an appealing alternative to precious metals. In this context, the employment of Cp*CoIII complexes have represented a tremendous advance in cobalt catalysis, since they have the potential to promote a wide variety of C–C and C–heteroatom bond-forming reactions, via putative cyclometalated cobalt(III) species. Despite this significant progress, these cobalt systems are still at their infancy compared to Rh- or Pd-based ones, essentially due to the limited fundamental organometallic understanding of these systems. The investigation of the underlying reaction mechanisms of these transformations has been hampered by the difficulty to detect/isolate key intermediates. Challenged by the lack of fundamental knowledge of these transformations, in this Doctoral thesis we explore: i) the design and development of novel synthetic routes for accessing well-defined and stable cobalt metallacycles, analogous to proposed key reactive intermediates; ii) the employment of these Cp*CoIII metallacycles not only for unravelling previous inaccessible mechanistic intricacies of selected Cp*CoIII-catalyzed processes but also for improving their efficiency; and finally, iii) the participation and/or effect of some additives in different benchmark transformations. The fundamental knowledge generated during this Doctoral Thesis has led to important breakthroughs in cobalt catalysis, specially at molecular level