<p>Bacterial L-asparaginases (E.C.3.5.1.1) are enzymes that catalyze the hydrolysis of L-asparagine to aspartic acid. For the past 30 years these enzymes have been used as therapeutic agents in the treatment of acute childhood lymphoblastic leukemia. The presence of a low rate glutaminase activity however causes serious side-effects to patients in treatment, as glutamine depletion give rise to neurotoxicity, anaphylaxis, and other hypersensitivity reactions. The interest in the enzyme from Erwinia carotovora originates from the fact that it shows a decreased glutaminase activity, and therefore the enzyme is expected to exhibit fewer side effects when used in therapy.</p><p>The main focus of this thesis is the crystal structure determination of L-asparaginase from Erwinia carotovora in the presence of aspartic acid at 2.5 Å resolution. The structure was refined to an R/Rfree factor of 19.9/28.6 with good stereochemistry.</p><p>L-Asparaginases are homotetrameric enzymes with a known 222 symmetry and an identical fold. The Erwinia carotovora asparaginase consists of eight monomers of 330 amino acid residues each. In this case the enzyme is active as a dimer of tetramers. The two tetramers have an inner twofold non-crystallographic symmetry. Each monomer forms two identifiable domains a large N-domain and a small C-domain. The active sites are found at a topological switch-point between those domains.</p>

<p>The applications of magnetic materials are related to their magnetic and crystal structure as well as electronic properties. In this thesis, mainly experimental methods have been focussed on novel materials and bulk materials. A selection of materials were studied by several techniques like Mössbauer spectroscopy, X-ray and neutron diffraction and magnetisation measurements.</p><p>New technology allow us to prepare artificial materials with unic magnetic properties. Magnetic multilayers are very interesting not only from phenomenological point of view but also as good applications materials. In this work will be shown some results from Fe/V and Fe/Co multilayer system</p><p>The (Fe_1-xMn_x)₃P system has been studied at both ends of the composition range. At the Fe-rich end, compounds exhibiting ferromagnetic ordering are formed, while at the Mn-rich end, an antiferromagnetic coupling was discovered. The experimental results are supported by theoretical calculations.</p><p>Rare-earth compounds with focus on Fe_0.65Er_0.2B_0.15 were studied by means of traditional Mössbauer spectroscopy, Monochromatic Circular Polarized Mössbauer Spectroscopy, X-ray diffraction and magnetic mesurements. This compound shows interesting behaviour of Fe magnetic moment at low and room temperature.</p><p>The first magnetic studies on rhombohedral Li₃Fe₂(PO₄)₃ at low temperature has also been made and an antiferromagnetic structure was revealed.</p>

Microporous materials have a wide range of important applications in separation, gas adsorption, ion-exchange and catalysis. Open-framework germanates are a family of microporous compounds and are of particular interest. This thesis focuses on the synthesis and characterization of new open-framework germanates as well as introducing the transition-metal nickel into germanate structures. One new microporous germanosilicate, SU-78 and four new open-framework germanates, SU-74, SU-75, SU-69 and SU-76 have been obtained by using organic molecules as structure directing agents (SDAs). The incorporation of nickel and organic SDAs in the synthesis resulted in five novel nickel germanates, SUT-1, SUT-2, SUT-3, SUT-4 and SUT-5, in which nickel complexes act either as framework-forming components or as structure directing agents. The general synthesis route is described and the variables that affect the synthesis products are summarized. Different techniques applied on the characterization of chemical and physical properties of the products are also introduced. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Submitted. Paper 2: Submitted. Paper 3: Submitted. Paper 5: Manuscript.</p>

Novel open-framework germanates and open low-dimensional structures were synthesized and characterized. Their crystal structures were solved by single crystal X-ray diffraction or X-ray powder diffraction combined with other techniques. Although related open-framework materials, such as zeolites, are of interest for the ability to selectively accommodate guest species in their rings, pores and channels, germanates are primarily of interest for their unique structural properties. Compared to aluminosilicate-based zeolites, germanium oxides readily form frameworks with extra-large rings and low framework density. The formation of elegant germanate architectures is attributed to the unique Ge-O bond geometries compared to Si-O, and the tendency to form large clusters. This thesis is to serve as an introduction to germanate synthesis, structures and characterization. Structures are categorized in accordance to their building units; the Ge7X19 (Ge7), Ge9X25-26 (Ge9) and Ge10X28 (Ge10) (X = O, OH, or F) clusters. Structure determination techniques as well as the characterization techniques used to examine the properties of the materials are presented. While most of the discussed techniques have routinely been used to study crystalline open-frameworks, we introduce the use of infrared spectroscopy for the identification of cluster types, valuable for structure determination by X-ray powder diffraction. Structures and properties of the novel materials ASU-21, SU-62, SU-63, SU-64, SU-65, SU-66, SU-71, SU-72, SU-73, SU-74, SU-75 and SU-JU-14 are described and put into context with previously known structures. The novel structures are all built of the Ge7, Ge9 or Ge10 clusters, and vary from a framework with novel topology to the first open zero-dimensional germanate cavities built of such clusters. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 4: Submitted. Paper 6: Submitted. Paper 7: Manuscript. Paper 8. Manuscript. Paper 10: Unpublished book chapter.</p><p> </p>

With the aim of finding alternative reaction media for the synthesis of subvalent main group and transition metal cluster compounds, traditionally made through solid state reactions or in superacidic media, different alternative reaction media have been explored in this work. Room-temperature ionic liquids are amongst the more unconventional reaction media used. The syntheses performed have been aimed at both anionic and cationic cluster and the main tools used for characterization have been different X-ray diffraction and spectroscopic techniques. Selected ionic liquids have along with dichloromethane been shown to work as alternative reaction media for room temperature synthesis of the Bi5[GaCl4]3 salt. The salt containing the subvalent naked bismuth polycation Bi5 3+ was isolated from reduction reactions of BiCl3 in Ga/GaCl3-dichloromethane respectively Ga/GaCl3-ioinc liquid media. Three different classes of ionic liquids based on phosphonium-, imidazolium- and pyrrolidinium- salts have been used in synthesis. Homopolyatomic clusters from the lighter Group 15 element arsenic have also been studied. Solutions from the oxidative and reductive reaction routes of arsenic and AsCl3 in Lewis acidic toluene media were studied by EXAFS spectroscopy. The results were evaluated using molecular dynamics simulations of arsenic clusters. A discussion on how the calculated As4 cluster model relates to the experimental data resulted from this study. In terms of homopolyatomic anionic clusters the [K+(2,2,2-crypt)]2Ge9 2- compound containing the naked Ge9 2- anionic cluster has been isolated. The crystallographic investigation of [K+(2,2,2-crypt)]2Ge9 2- shows Zintl cluster anion Ge9 2- to be tricapped trigonal-prismatic with a symmetry very close to D3h. A chemical bonding analysis reveals two local minima of D3h symmetry and the cluster interaction scheme to be based on highly delocalised bonding. Ligand supported transition metal clusters from tungsten and palladium have also been prepared. Reduction of WCl6 in a reaction mixture of ionic liquid and co-solvent toluene resulted in tritungsten decachloride; W3Cl10(MeCN)3, being formed. Furthermore, palladium sandwich compounds; [Pd2(Ga2Cl7)(C7H8)2], [Pd2(GaCl4)(C9H12)2]∙C9H12 and [Pd2(Ga2Cl7)(C6H5Cl)2] have been prepared using GaCl3-arene reaction media. / <p>QC 20121212</p>

The applications of magnetic materials are related to their magnetic and crystal structure as well as electronic properties. In this thesis, mainly experimental methods have been focussed on novel materials and bulk materials. A selection of materials were studied by several techniques like Mössbauer spectroscopy, X-ray and neutron diffraction and magnetisation measurements. New technology allow us to prepare artificial materials with unic magnetic properties. Magnetic multilayers are very interesting not only from phenomenological point of view but also as good applications materials. In this work will be shown some results from Fe/V and Fe/Co multilayer system The (Fe1-xMnx)3P system has been studied at both ends of the composition range. At the Fe-rich end, compounds exhibiting ferromagnetic ordering are formed, while at the Mn-rich end, an antiferromagnetic coupling was discovered. The experimental results are supported by theoretical calculations. Rare-earth compounds with focus on Fe0.65Er0.2B0.15 were studied by means of traditional Mössbauer spectroscopy, Monochromatic Circular Polarized Mössbauer Spectroscopy, X-ray diffraction and magnetic mesurements. This compound shows interesting behaviour of Fe magnetic moment at low and room temperature. The first magnetic studies on rhombohedral Li3Fe2(PO4)3 at low temperature has also been made and an antiferromagnetic structure was revealed.

Signaling pathways control the fate of the cell. For example, they promote cell survival or commit the cell to death (apoptosis) in response to cell injury or developmental stimuli, decisions, which are vital for the proper development and functioning of metazoan. Tight control of such pathways is essential; dysregulation of apoptosis can disrupt the delicate balance between cell proliferation and cell death ending up in pathological processes, including cancer, autoimmunity diseases, inflammatory diseases, or degenerative disorders. We have used a structural genomic approach to study the structure and function of key proteins involved in apoptosis and lipid signaling: the antiapoptotic Bcl-2 family member Bfl-1 in complex with a Bim peptide, the BIR domains of the Inhibitor of Apoptosis (IAP) family members, cIAP2 and NAIP and the a lipid kinase YegS. The structural analysis of the apoptosis regulatory proteins has revealed important information on the structural determinants for recognition of interacting proteins, which can now assist in the development of therapeutic drugs for human diseases. The structural and complementing biochemical studies of the lipid kinase YegS have reveled the first detailed information on a lipid kinase and explained important aspects of its structure-function relationship. Finally, one subject of this work aim to solve what is arguably the most challenging problem in structural projects – to obtain a high production level of proteins suitable for structural studies. We have developed a highthroughput protein solubility screening, the colony filtration (CoFi) blot, which allows soluble clones to be identified from large libraries of protein variants and now constitute a powerful tool for solving difficult protein production problems.

Pyridazines are heterocyclic compounds with an N-N bond in their ring structure. Heterocyclic aromatic compounds are of great interest as a result of their novel properties and commercial applications. Our current research is focused on the potential role of pyridazines in next generation electronic devices that utilize organics as the semiconducting material. The synthesis of 5, 6-fused ring pyridazines beginning from fulvenes (Scheme 1) is described herein. These fused heterocycles will serve as synthetic models and building blocks for potential organic or organometallic conducting polymers. Our goal was to modify the route of Snyder et al. previously reported for the direct synthesis of pyridazine 2. This required improved synthesis of fulvene 1 and higher yields of 5. Additionally, a thorough analysis of the x-ray data was obtained to better understand the 3D aspects of this compound (pyridazine 2).This route was quite general and features an efficient and convenient synthesis. Single crystal X-ray analysis confirms the molecular structure of pyridazine 2. Full synthesis and characterization of newly formed pyridazine 2 and Fulvene 1 are reported.

The main topic of this thesis is the development of computational search methods that are useful in drug design applications. The emphasis is on exhaustiveness of the search method such that it can guarantee a certain level of geometric accuracy. In particular, the following two problems are addressed: (i) Prediction of binding mode of a drug molecule to a receptor and (ii) prediction of crystal structures of drug molecules. Predicting the binding mode(s) of a drug molecule to a target receptor is pivotal in structure-based rational drug design. In contrast to most approaches to solve this problem, the idea in this work is to analyze the search problem from a computational perspective. By building on top of an existing docking tool, new methods are proposed and relevant computational results are proven. These methods and results are applicable for other place-and-join frameworks as well. A fast approximation scheme for the docking of rigid fragments is described that guarantees certain geometric approximation factors. It is also demonstrated that this can be translated into an energy approximation for simple scoring functions. A polynomial time algorithm is developed for the matching phase of the docked rigid fragments. It is demonstrated that the generic matching problem is NP-hard. At the same time the optimality of the proposed algorithm is proven under certain scoring function conditions. The matching results are also applicable for some of the fragment-based de novo design methods. On the practical side, the proposed method is tested on 829 complexes from the PDB. The results show that the closest predicted pose to the native structure has the average RMS deviation of 1.06 °A. The prediction of crystal structures of small organic molecules has significantly improved over the last two decades. Most of the new developments, since the first blind test held in 1999, have occurred in the lattice energy estimation subproblem. In this work, a new efficient systematic search method that avoids random moves is proposed. It systematically searches through the space of possible crystal structures and conducts search space cuts based on statistics collected from the structural databases. It is demonstrated that the fast search method for rigid molecules can be extended to include flexible molecules as well. Also, the results of some prediction experiments are provided showing that in most cases the systematic search generates a structure with less than 1.0°A RMSD from the experimental crystal structure. The scoring function that has been developed for these experiments is described briefly. It is also demonstrated that with a more accurate lattice energy estimation function, better results can be achieved with the proposed robust search method.

HfO2 is a popular replacement for SiO2 in modern CMOS technology. It is used as the gate dielectric layer isolating the transistor channel from the gate. For this application, certain material property demands need to be met, most importantly, a high static dielectric constant is desirable as this positively influences the effectiveness and reliability of the device. Previous theoretical calculations have found that this property varies with the crystal structure of HfO2; specifically, the tetragonal structure possesses the highest dielectric constant (~70 from theoretical calculations) out of all possible stable structures at atmospheric pressure, with the cubic phase a far second (~29, also calculated). Following the results from previous experimental work on the phase formation of sputtered HfO2, this study investigates the possibility of producing thin films of HfO2 with the cubic or tetragonal structure by the addition of nitrogen to a reactive sputtering process at various deposition temperatures. Also, a new physical vapor deposition method known as High Power Impulse Magnetron Sputtering (HiPIMS) is employed for its reported deposition stability in the transition zone of metal-oxide compounds and increased deposition rate. Structural characterization of the produced films shows that films deposited at room temperature with a low N content (~6 at%) are mainly composed of amorphous HfO2 with mixed crystallization into t-HfO2 and c-HfO2, while pure HfO2 is found to be composed of amorphous HfO2 with signs of crystallization into m-HfO2. At 400o C deposition temperature, the crystalline quality is enhanced and the structure of N incorporated HfO2 is found to be c-HfO2 only, due to further ordering of atoms in the crystal lattice. Optical and dielectric characterization revealed films with low N incorporation (&lt; 6 at%) to be insulating while these became conductive for higher N contents. For the insulating films, a trend of increasing static dielectric constant with increasing N incorporation is found.