abstract: One of the greatest problems facing society today is the development of a sustainable, carbon neutral energy source to curb the reliance on fossil fuel combustion as the primary source of energy. To overcome this challenge, research efforts have turned to biology for inspiration, as nature is adept at inter-converting low molecular weight precursors into complex molecules. A number of inorganic catalysts have been reported that mimic the active sites of energy-relevant enzymes such as hydrogenases and carbon monoxide dehydrogenase. However, these inorganic models fail to achieve the high activity of the enzymes, which function in aqueous systems, as they lack the critical secondary-shell interactions that enable the active site of enzymes to outperform their organometallic counterparts. To address these challenges, my work utilizes bio-hybrid systems in which artificial proteins are used to modulate the properties of organometallic catalysts. This approach couples the diversity of organometallic function with the robust nature of protein biochemistry, aiming to utilize the protein scaffold to not only enhance rates of reaction, but also to control catalytic cycles and reaction outcomes. To this end, I have used chemical biology techniques to modify natural protein structures and augment the H2 producing ability of a cobalt-catalyst by a factor of five through simple mutagenesis. Concurrently I have designed and characterized a de novo peptide that incorporates various iron sulfur clusters at discrete distances from one another, facilitating electron transfer between the two. Finally, using computational methodologies I have engineered proteins to alter the specificity of a CO2 reduction reaction. The proteins systems developed herein allow for study of protein secondary-shell interactions during catalysis, and enable structure-function relationships to be built. The complete system will be interfaced with a solar fuel cell, accepting electrons from a photosensitized dye and storing energy in chemical bonds, such as H2 or methanol. / Dissertation/Thesis / Doctoral Dissertation Biochemistry 2016

abstract: The exceptional mechanical properties of polymers with heterogeneous structure, such as the high toughness of polyethylene and the excellent blast-protection capability of polyurea, are strongly related to their morphology and nanoscale structure. Different polymer microstructures, such as semicrystalline morphology and segregated nanophases, lead to coordinated molecular motions during deformation in order to preserve compatibility between the different material phases. To study molecular relaxation in polyethylene, a coarse-grained model of polyethylene was calibrated to match the local structural variable distributions sampled from supercooled atomistic melts. The coarse-grained model accurately reproduces structural properties, e.g., the local structure of both the amorphous and crystalline phases, and thermal properties, e.g., glass transition and melt temperatures, and dynamic properties: including the vastly different relaxation time scales of the amorphous and crystalline phases. A hybrid Monte Carlo routine was developed to generate realistic semicrystalline configurations of polyethylene. The generated systems accurately predict the activation energy of the alpha relaxation process within the crystalline phase. Furthermore, the models show that connectivity to long chain segments in the amorphous phase increases the energy barrier for chain slip within crystalline phase. This prediction can guide the development of tougher semicrystalline polymers by providing a fundamental understanding of how nanoscale morphology contributes to chain mobility. In a different study, the macroscopic shock response of polyurea, a phase segregated copolymer, was analyzed using density functional theory (DFT) molecular dynamics (MD) simulations and classical MD simulations. The two models predict the shock response consistently up to shock pressures of 15 GPa, beyond which the DFT-based simulations predict a softer response. From the DFT simulations, an analysis of bond scission was performed as a first step in developing a more fundamental understanding of how shock induced material transformations effect the shock response and pressure dependent strength of polyurea subjected to extreme shocks. / Dissertation/Thesis / Doctoral Dissertation Mechanical Engineering 2017

Made available in DSpace on 2015-05-14T13:21:23Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2208268 bytes, checksum: a713e84bf72b1325038dab0816e190d4 (MD5) Previous issue date: 2009-11-27 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / In this work the origin of the π−π-staking conformation stability of 5S in the 8-acrylate phenylmenthol 5 was revisiting. The geometries of 5S and 5T conformers were optimized from HF method and the MPW1B95 functional; and the geometries of the 11S and 11T conformers have been optimized from HF, MP2 methods and MPW1B95 functional. All calculations were performed on 6-311 + + G (2d, 2p) 6d as level of calculation. Using the optimized geometries of 5S, 5T, 11S and 11T (from MPW1B95/6-311 + + G (2d, 2p) 6d), were performed 15 energy single-point calculations, investigating various computational methods (ab initio, DFT and semiempirical). We also described the spectroscopic (1H NMR) and theoretical (DFT and ab initio) studies of 3-naphytylpropylcrotonate (12) and 3- naphytylpropylsorbate (21). The geometries of 12S and 12T conformers have been optimized from MP2, HF methods and B3LYP, LSDA and MPW1B95 functionals using 6-311+G(d,p) as calculation level. Finally, we describe the synthesis of 12 and 21 (the unpublished) in 3 steps of each synthesis (19% and 22% respectively of total yields) and the trans geometries of 12T and 21T were characterized as the most stable in the conformational equilibrium of 12 and 21. / Neste trabalho a origem do motivo para a maior estabilidade da conformação de 5S no acrilato de 8-fenilmentol 5 foi investigada. As geometrias dos confôrmeros 5S e 5T foram otimizadas nos métodos HF e no funcional MPW1B95; e as geometrias dos confôrmeros 11S e 11T foram otimizadas nos métodos HF, MP2 e o funcional MPW1B95. Todos os cálculos usaram 6-311++G(2d,2p)6d como nível de cálculo. Usando as geometrias otimizadas de 5S, 5T, 11S e 11T (por MPW1B95/6-311++G(2d,2p)6d), foram efetuados 15 cálculos de energia no ponto, investigando metodologias computacionais variadas (ab initio, DFT e semiempirico). Descrevemos também o estudo espectroscópico (RMN 1H) e teórico (DFT e ab initio) do crotonato de 3-naftilpropila (12) e o sorbato de 3-naftilpropila (21). As geometrias dos confôrmeros de 12S e 12T foram otimizadas com os métodos MP2, HF e os Funcionais B3LYP, LSDA e MPW1B95 usando 6- 311+G(d,p) como nível de cálculo. Finalmente, descrevemos a síntese total de 12 e 21 (inéditas na literatura) em 3 etapas de síntese cada (19% e 22% respectivamente de rendimentos globais) e caracterizamos por 1H RMN a geometria trans 12T e 21T como a mais estável no equilíbrio conformacional de 12 e 21.

Ante la evidente necesidad de comprender los frecuentes cambios negativos que experimenta el planeta Tierra en los suelos, los ríos y la atmosfera y con la idea de intentar mitigar el cambio climático, aparece la química computacional como una rama de la química que nos permite estudiar y predecir diversas propiedadesfisicoquímicas de sistemas moleculares complejos de interés ambiental las cuales son, algunas veces, imposibles de estudiar de forma experimental. El presente artículo muestra un panorama molecular del comportamiento y características fisicoquímicas de algunos contaminantes atmosféricos estudiados a través de la química computacional / The urgent need to understand the frequent negative changes that the planet Earth suffer on its soil, rivers and atmosphere and the need to mitigate climate change makes computational chemistry stand out as a branch of chemistry that allows thestudy and prediction of different physicochemical properties of several complex molecular systems of environmental significance which are sometimes impossible to study in a laboratory. The present article shows a molecular overview of the behavior and physicochemical characteristics of some atmospheric pollutants studied through computational chemistry.

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Abstract The present thesis investigates the electronic structure of selected atoms and molecules in vapor phase. Electron spectroscopy is applied for studying the electronic transitions following excitation and ionization with electron and photon bombardment. The work focuses on the photoionization and Auger decay of selected noble gasses, and on the photoionization and Auger decay of core ionized or resonant excited alkali halide molecules. The experimental results are compared with theoretical predictions.

This thesis is concerned with the simulation of various electrochemical experiments and its application to electroanalysis. Chapter 1 outlines the fundamental principles of electrochemistry which are of importance for the reading of this thesis. Chapter 2 then outlines the methods used in the numerical simulation of electrochemical experiments. Chapters 3 and 4 are concerned with the electrochemistry of nanoparticles, and how this is affected by the presence of near wall hindered diffusion. In Chapter 3, a computational model to simulate anodic particle coulometry of nanoparticles in the presence of hindered diffusion is developed, and the effect of this hindered diffusion investigated. The model is then applied to simulate experimental data. Chapter 4 looks at the effect of hindered diffusion on the adsorption of nanoparticles on electrode surfaces, and investigates the effects of this adsorption on electrochemical experiments with nanoparticles generally. Chapters 5, 6 and 7 are concerned with band electrodes in isolation, in a pair and in an array respectively. In Chapter 5, a model to simulate double potential step chronoamperometry at an individual band electrode is developed, and used to successfully simulate experimental data. Chapter 6 looks at dual band electrodes used in generator-collector mode, and how this can be used to simultaneously measure the concentration of two species in solution. Chapter 7 looks at interdigitated arrays of band and ring electrodes in generator-collector mode, and develops a model to simulate cyclic voltammetry in both cases, as well as investigating under what conditions interdigitated ring arrays may be modelled as interdigitated band arrays. Chapter 8 develops a model to simulate chronoamperometry and cyclic voltammetry at porous electrodes, and investigates the consequences for electroanalysis of having a porous layer. Finally, Chapter 9 investigates the Marcus-Hush theory of electron transfer kinetics, and looks at the effect of the kinetically limited currents resulting from this theory to the equivalence relation between microdisc electrodes and sphere-on-a-surface electrodes.

Ce travail de thèse vise à étudier l'endommagement de l'ADN, de la formation de lésions à leur réparation par des méthodes de modélisation moléculaire. Plusieurs projets ont pris forme dans ce contexte, lesquels peuvent être classés en trois grandes catégories. D'un côté, nous nous sommes intéressés la formation de lésions induites par des agents mutagènes. Nous avons étudié les mécanismes de formation de la 8-oxo-7,8-dihydroguanine (8oxoG), mais aussi le caractère de photosensibilisateur endogène de la pyrimidine 6-4 pyrimidone (6-4PP), et la photosensibilisation de l'ADN par deux anti-inflammatoires : le kétoprofène et l'ibuprofène. D'un autre côté, les propriétés mécaniques de l'ADN endommagé ont été simulées. La structure de lésions complexes est d'une importance capitale pour comprendre la manière dont elles sont réparées. Malheureusement, seulement peu de structures RMN et cristallographiques sont disponibles à ce jour. Pour pallier à ce manque et obtenir des informations sur leur dynamique, nous avons étudié un panel de lésions complexes : les clusters de sites abasiques, les pontages inter-brins, et la photolésion 6-4PP. De même, nous nous sommes penchés sur les modes d'interaction de certaines polyamines avec l'ADN, ces molécules étant connues pour interagir avec la double hélice. Enfin, latroisième partie de cette thèse concerne les interactions ADN-enzyme de réparation. En perspective avec l'étude de clusters d'abasiques, nous avons étudié le comportement dynamique du même système, cette fois-ci en interaction avec l'endonucléase APE1. Nous nous sommes également penchés sur les interactions entre la glycosylase Fpg avec un oligonucléotide contenant un tandem de lésions 8-oxoG d'un côté, etun cluster de lésions 8-oxoG - site abasique de l'autre. Ces multiples projets ont permis l'accumulation de nouvelles connaissances à propos des lésions complexes de l'ADN, et ont également apporté un appuicomputationnel aux expérimentations, qui peuvent se révéler très délicates dans ce domaine. Nos résultats ouvrent de larges perspectives dans le domaine de la pharmacologie, la cosmétique et plus généralementla compréhension du vivant / This thesis work is focused on the theoretical modelling of DNA damages, from formation to repair. Several projects have been led in this framework, which can be sorted into three different parts. One on hand, we studied complex DNA reactivity. It included a study about 8-oxo-7,8-dihydroguanine (8oxoG) mechanisms of formation, a project concerning the UV-induced pyrimidine 6-4 pyrimidone (6-4PP) endogenous photosensitizer features, and an other one about DNA photosensitizationby nonsteroidal anti-inflammatory drugs (ie ketoprofen and ibuprofen). On the other hand, we investigated mechanical properties of damaged DNA. The structural signature of a DNA lesion is of major importance for their repair, unfortunately only few NMR and X-ray structures of such systems are available. In order to gain insights into their dynamical structure, we investigated a series of complex damages : clustered abasic sites, interstrand cross-links, and the 6-4PP photolesion. Likewise, we studied the interaction modes DNA with several polyamines, which are well known to interact with the double helix, but also with the perspective to model DNA-protein cross-linking. The third part concerned the study of DNA interactions with repair enzymes. In line with the structural study about clustered abasic sites, we investigated the dynamics of the same system, but this time interacting with the APE1 endonuclease. We also studied interactions between the Fpg glycosylase with an oligonucleotides containing tandem 8-oxoG on one hand and 8-oxoG - abasic site as multiply damaged sites. Thus, we shed new lights on damaged DNA reactivity, structure and repair, which provides perspectives for biomedicine and life's mechanisms understanding as we begin to describe nucleosomal DNA

A series of para-substituted phenylethylamine analogues bound to the enzyme aromatic amine dehydrogenase have been simulated using quantum mechanical electronic structure calculations and molecular mechanical molecular dynamics simulations. Trends have been verified connecting bond dissociation energy (and thus driving force) to observed rate constants and activation enthalpy. Trends have been identified in connecting statistics drawn from molecular dynamics simulations and the temperature dependence of the kinetic isotope effect, notably that as the temperature dependence of the kinetic isotope effect increases the flexibility of the promoting vibration decreases. This is explained as being more effected by thermal energy put into the system, and therefore more affected by temperature.

Accumulation and aggregation of the 42-residue amyloid-[beta] (A[beta]) protein fragment, which originates from the cleavage of amyloid precursor protein by beta and gamma secretase, correlates with the pathology of Alzheimer's disease (AD). Possible therapies for AD include peptides based on the A[beta] sequence, and recently identified small molecular weight compounds designed to mimic these, that interfere with the aggregation of A[beta] and prevent its toxic effects on neuronal cells in culture. Here, we use molecular dynamics simulations to compare the mode of interaction of an active (LPFFD) and inactive (LHFFD) [beta]-sheet breaker peptide with an A[beta] fibril structure from solid state NMR studies. We found that LHFFD had a weaker interaction with the fibril than the active peptide, LPFFD, from geometric and energetic considerations, as estimated by the MM/PBSA approach. Cluster analysis and computational alanine scanning identified important ligand-fibril contacts, including a possible difference in the effect of histidine on ligand-fibril [pi]-stacking interactions, and the role of the proline residue establishing contacts that compete with those essential for maintenance of the inter-monomer [beta]-sheet structure of the fibril. Our results show that molecular dynamics simulations can be a useful way to classify the stability of docking sites. These mechanistic insights into the ability of LPFFD to reverse aggregation of toxic A[beta] will guide the redesign of lead compounds, and aid in developing realistic therapies for AD and other diseases of protein aggregation. We have also performed long explicit solvent MD simulations of unliganded amyloid fibril in three putative protonation states, in order to better understand the energetic and mechanical features of the fibril receptor. Over 100 ns MD simulations, the trajectories where fibril has Glu11 and Glu22 side-chains protonated exhibit the least deviation from the initial solid state NMR structures. Free energy calculations on these rajectories suggest that the weakest fibril interface lies in the lateral rather than transverse direction and that there is little dependence on whether the lateral interface is situated at the edge or middle of the fibril. This agrees with recent reported steered molecular dynamics calculations. Secondly, in an effort to improve the ability of atomistic simulation techniques to directly resolve protein tertiary structure from primary amino acid sequence, we explore the use of a molecular dynamics technique based on swarm intelligence, called SWARM-MD, to identify the native states of two peptides, polyalanine and AEK17, as well as Trp-cage miniprotein. We find that the presence of cooperative swarm interactions significantly enhanced the efficiency of molecular dynamics simulations in predicting native conformation. However, it also is evident that the presence of outlying simulation replicas can adversely impact correctly folded replica structures. By slowly removing the swarm potential after folding simulations, the negative effect of the swarm potential can be alleviated and better agreement with experiment obtained.