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The need for cleaner and more efficient alternative energy sources is becoming urgent as concerns mount about climate change wrought by greenhouse gas emissions. Solid oxide fuel cells (SOFCs) are one of the most efficient options if the goal is to reduce emissions while still operating on fossil energy resources. One of the foremost problems in SOFCs that causes efficiency loss is the polarization resistance associated with the oxygen reduction reaction(ORR) at the cathodes. Hence, improving the cathode design will greatly enhance the overall performance of SOFCs. Lanthanum nickelate, La2NiO4+δ (LNO), is a mixed ionic and electronic conductor that has competitive surface oxygen exchange and transport properties and excellent electrical conductivity compared to perovskite-type oxides. This makes it an excellent candidate for solid oxide fuel cell (SOFC) applications. It has been previously shown that composites of LNO with Sm0.2Ce0.8O2-δ (SDC20) as cathode materials lead to higher performance than standalone LNO. However, in contact with lanthanide-doped ceria, LNO decomposes resulting in free NiO and ceria with higher lanthanide dopant concentration. In this study, the aforementioned instability of LNO has been addressed by compositional tailoring of LNO: lanthanide doped ceria (LnxCe1-xO2,LnDC)composite. By increasing the lanthanide dopant concentration in the ceria phase close to its solubility limit, the LNO phase has been stabilized in the LNO:LnDC composites. Electrical conductivity of the composites as a function of LNO volume fraction and temperature has been measured, and analyzed using a resistive network model which allows the identification of a percolation threshold for the LNO phase. The thermomechanical compatibility of these composites has been investigated with SOFC systems through measurement of the coefficients of thermal expansion. LNO:LDC40 composites containing LNO lower than 50 vol%and higher than 40 vol% were identified as being suitable to incorporate into full button cell configuration from the standpoint of thermomechanical stability and adequate electrical conductivity. Proof-of-concept performance comparison for SOFC button cells manufactured using LNO: La0.4Ce0.6O2-δ composite to the conventional composite cathode materials has also been provided. This thermodynamics-based phase stabilization strategy can be applied to a wider range of materials in the same crystallographic family, thus providing the SOFC community with alternate material options for high performance devices.

PEGylation of protein side-chains has been used for more than 30 years to enhance the pharmacokinetic properties of protein drugs, and has been enabled by the recent development of many chemoselective reactions for protein side-chain modification. However, there are no structure- or sequence-based guidelines for selecting sites that provide optimal PEG-based pharmacokinetic enhancement with minimal loss to biological activity. Chapter 1 is a brief introduction to protein PEGylation. In chapter 2 we use the WW domain of the human protein Pin 1 (WW) as a model system to probe the impact of PEG on protein conformational stability. Using a combination of experimental and theoretical approaches, we develop a structure-based method for predicting which sites within WW are most likely to experience PEG-based stabilization, and show that this method correctly predicts the location of a stabilizing PEGylation site within the chicken Src SH3 domain. PEG-based stabilization in WW is associated with enhanced resistance to proteolysis, is entropic in origin, and likely involves disruption by PEG of the network of hydrogen-bound solvent molecules that surround the protein. Chapter 3 shows that PEG-based stabilization of the WW domain depends strongly on the identity of the PEG-protein linker, with the most stabilizing linkers involving conjugation of PEG to an Asn side-chain amide nitrogen. Chapter 4 investigates the interplay between structure-based guidelines for PEG-base stabilization developed in chapter 2 and the different chemistries explored in chapter 3.

The current understanding of the mechanical properties and deformation behavior of some individual phases in titanium alloys is limited due to the fine scale at which these phases precipitate within the β-phase matrix. The α and ω phases represent the most widely observed phases in titanium alloys depending on the alloy composition and also the heat treatment procedure adopted during processing. The possibility of precipitating ω-phase depends on the content of the β-stabilizers within the system. Although a significant compositional partitioning occurs within ω-phase upon aging treatment, the knowledge of ω-phase mechanical properties as a function of composition is very limited. The initial part of the current work focuses on the effect of common β-stabilizers elements on the phase stability and mechanical properties of the ω-phase using first-principles calculations. A relation between the bonding nature, the phase stability, and elastic properties was proposed. Thereafter αʺ martensitic phase was investigated in Ti-Nb and Ti-Nb-O alloys. The phase stability and martensitic start temperature of αʺ-phase was studied as a function of Nb and oxygen content. Also, the effect of the lattice shear distortion induced by oxygen atom on stabilizing β-phase was investigated. Subsequently the effect of the β-stabilizers' elements on stacking faults energy and ductility in α-Ti alloys was studied. Both prismatic and basal slip system were investigated with different concentration of β-stabilizers at the slip plane. Lastly, while the Tadmor and Bernstein model was employed to predict the partial dislocation emission and twinning propensity, the Rice criterion was used to estimate the effect of different β-stabilizers on the ductility of α-Ti alloys.

<p>Thermodynamic stability measurements on proteins and protein-ligand complexes can offer insights not only into the fundamental properties of protein folding reactions and protein functions, but also into the development of protein-directed therapeutic agents to combat disease. Conventional calorimetric or spectroscopic approaches for measuring protein stability typically require large amounts of purified protein. This requirement has precluded their use in proteomic applications. Stability of Proteins from Rates of Oxidation (SPROX) is a recently developed mass spectrometry-based approach for proteome-wide thermodynamic stability analysis. Since the proteomic coverage of SPROX is fundamentally limited by the detection of methionine-containing peptides, the use of tryptophan-containing peptides was investigated in this dissertation. A new SPROX-like protocol was developed that measured protein folding free energies using the denaturant dependence of the rate at which globally protected tryptophan and methionine residues are modified with dimethyl (2-hydroxyl-5-nitrobenzyl) sulfonium bromide and hydrogen peroxide, respectively. This so-called Hybrid protocol was applied to proteins in yeast and MCF-7 cell lysates and achieved a ~50% increase in proteomic coverage compared to probing only methionine-containing peptides. Subsequently, the Hybrid protocol was successfully utilized to identify and quantify both known and novel protein-ligand interactions in cell lysates. The ligands under study included the well-known Hsp90 inhibitor geldanamycin and the less well-understood omeprazole sulfide that inhibits liver-stage malaria. In addition to protein-small molecule interactions, protein-protein interactions involving Puf6 were investigated using the SPROX technique in comparative thermodynamic analyses performed on wild-type and Puf6-deletion yeast strains. A total of 39 proteins were detected as Puf6 targets and 36 of these targets were previously unknown to interact with Puf6. Finally, to facilitate the SPROX/Hybrid data analysis process and minimize human errors, a Bayesian algorithm was developed for transition midpoint assignment. In summary, the work in this dissertation expanded the scope of SPROX and evaluated the use of SPROX/Hybrid protocols for characterizing protein-ligand interactions in complex biological mixtures.</p> / Dissertation

Title: Symmetrical aminophosphinates Author: Bc. Soňa Procházková Department of Inorganic Chemistry, Faculty of Science, Charles University Supervisor: RNDr. Vojtěch Kubíček, Ph.D. Supervisor's email address: kubicek@natur.cuni.cz ABSTRACT Two types of α-aminophosphinates were prepared and studied: phosphinate analogues of iminodiacetic acid − aminobis(methyl(hydroxymethyl)phosphinic acid) (IDPhm ) and aminobis(methyl(2-carboxyethyl)phosphinic acid) (IDPce ), and bis(aminomethyl- phosphinates) − (hydroxy(fenyl)methylen)bis(aminomethylphosphinic acid) (PheOHABPin) and (methylen)bis(aminomethylphosphinic acid) (ABPin). All prepared compounds were fully characterized (by NMR, MS, elemental analysis). One crystal structure was determined by X-ray singlecrystal analysis. The diphosphinates were synthesized by Mannich type reaction, whereas the bis(aminomethylphosphinates) were prepared by multistep synthesis including reactive silylesters. Compounds were prepared in moderate or good yields Acid-base and coordination properties of ligands were investigated and compared by potentiometric and NMR titrations. The values of protonation constants of aminogroups, which determine stability of complexes, showed surprising results. An extremely low basicity of nitrogen atom was found in diphosphinates. So, these compounds...

Title: Bifunctional ligands for copper(II) complexation Author: Bc. Martina Benešová Supervisor: doc. RNDr. Jan Kotek, Ph.D. Institution: Department of Inorganic Chemistry, Faculty of Science, CU in Prague Author's e-mail: EvaGlaser@seznam.cz ABSTRACT The main aim of this thesis was preparation of macrocyclic ligands based on 1,4,8,11- tetraazacyclotetradecane skeleton, which is suitable for selective complexation of divalent copper, and study of their properties. These ligands are suggested for potential utilization in nuclear medicine. Cyclam macrocycle was modified to bear one coordinating aminobenzylphospinate pendant arm (compound L1) or monophosphinate-bis(phosphonate) pendant arm (compound L2). During the synthesis, the skeleton was protected in positions 1, 4 and 8. In the frame of this work the synthesis of both targeted products was developed. Furthermore, a study of the thermodynamic, kinetic and coordination properties of ligand L2 was investigated by UV/VIS spectrophotometry and potentiometric titrations. A model bioconjugation of ligand L1 with primary amine was also studied. KEYWORDS Cyclam, phosphinates, phosphonates, nuclear medicine, copper(II) complexes, kinetic inertness, thermodynamic stability.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the upper and lower motor neurons causing muscle atrophy and paralysis followed by death. Aggregates containing superoxide dismutase (SOD1) are found as pathological hallmark in diseased ALS patients. Consequently ALS is regarded as a protein misfolding disorder like Alzheimer’s disease and Parkinson’s disease. So far, little is known about the cause and mechanism behind SOD1 aggregation but the inherent property of all polypeptide chains to form stable aggregated structures indicates that the protein misfolding diseases share a common mechanism. Our results show that SOD1 aggregation starts from the globally unfolded state, since fibrillation is fastest at full occupancy of denatured protein induced either by chemical denaturation or mutation. Even so, the fibrillation rate shows a surprisingly weak dependence on the concentration of globally unfolded SOD1 indicating fibril fragmentation as the dominant mechanism for aggregate formation. This is further supported by the observation that the SOD1 sample has to be mechanically agitated for fibrillation to occur.  Interestingly, we observe a similar SOD1 aggregation behaviour in vivo, where the survival times of ALS transgenic mice correlates with mutant stability, and aggregate growth depends weekly on the concentration of unfolded monomer. Additionally, in-cell NMR measurements reveal that in live cells the thermodynamic equilibrium is shifted towards the unfolded state of SOD1, which is also more fully extended than in vitro. This suggests that the globally unfolded aggregation competent protein is more abundant in the crowded environment in vivo than dilute in vitro conditions. Finally, antibody analysis of aggregates from ALS transgenic mice reveals the existence of aggregate strains involving different parts of the protein depending on mutation, which may offer an explanation for the various disease phenotypes observed in ALS. Altogether these findings provide important clues for understanding SOD1 aggregation with implications for ALS, as well as other protein misfolding diseases.

The aim of this thesis was to prepare monoamide of macrocycle H3NOTA, which was prepared by multiple step synthesis. Ligand was characterized by NMR, MS and X-ray difraction analysis. Acid-base properties were studied by potentiometric titrations. Four protonation constants pKa`s were found and these protonation constants are lower than pKa`s of H3NOTA. Coordination properties with selected metal ions from the first row of transition metal, metal ions of biological interest and with lithium ions were investigated by potentiometric titration. Stability constants show that monoethylamide derivative of macrocycle H3NOTA forms complexes with lower stability than diethylamide derivative of macrocycle H3NOTA. Stability constants for complexes which contains amide group are lower than for H3NOTA complexes. Kinetics of Ga3+ complexation was investigated at different pH by 71 Ga NMR. The rate constants of and half-lives of complexation were determined at pH = 1. The rate constant was higher and the half-life of complexation was shorter than for H3NOTA ligand. Key words: macrocyclic complexes, thermodynamic stability, formation kinetics, radiopharmaceutical

The aim of this work was to synthesize and study acid-base and coordination properties of ligands bearing a neutral or negative charge on their pendant arms. Acid-base properties of two ligands and thermodynamic stability of their complexes with gallium, copper, and zinc ions were studied using potentiometry, UV-Vis and NMR. Solid state structure of one of the ligands and its complex with copper ion was studied using RTG structural analysis. Structure of complexes in solution was studied using methods of computational chemistry.