Nature__s own building block, peptide/protein derived materials have been of great interest for supramolecular chemists. The amino acids in peptides/proteins are linked via amide bonds, which makes... Show moreNature__s own building block, peptide/protein derived materials have been of great interest for supramolecular chemists. The amino acids in peptides/proteins are linked via amide bonds, which makes them more stable against degradation as compared to other natural materials such as oligonucleotides. Peptides adopt a secondary structure which is determined by their amino acid sequence resulting in a structure with a specific fold like a beta sheet, a helix or a random coil conformation.These secondary structures can govern the supra-molecular structure of the macromolecule to achieve specific function. Peptides can be short, such as dipeptides or as long as a small protein, which are able to selfassemble into a designed nanostructure and thus providing a wide choice of biomaterials for a chemical biologist. In last decade, peptides have been shown to have great versatility and inherent high affinity for their target to carry out various functions which is the scope of this thesis presented here. Show less
Glycosidases are a large, evolutionary conserved enzyme family that catalyze the hydrolysis of glycosidic linkages of glycopolymers. These enzymes are involved in many (patho)physiological... Show moreGlycosidases are a large, evolutionary conserved enzyme family that catalyze the hydrolysis of glycosidic linkages of glycopolymers. These enzymes are involved in many (patho)physiological processes and they are applied in the glycopolymer assembly and biotechnological industry. The research described in this Thesis aims to develop inhibitors (mechanism-based and competitive) and activity-based probes for glycosidases using the naturally occurring molecule cyclophellitol as template. Different cyclophellitol derivatives have been synthesized and they could be used to study the role of glycosidases in different (patho)physiological and biotechnological processes. Show less
This thesis uses the surface science approach to address questions regarding the interaction of oxygen with platinum and its subsequent reaction with carbon monoxide. A Pt(111) single crystal... Show moreThis thesis uses the surface science approach to address questions regarding the interaction of oxygen with platinum and its subsequent reaction with carbon monoxide. A Pt(111) single crystal surface is used as a model for the catalyst. Chapter 1 provides an overview of the literature on the subject. The description of employed experimental techniques and their backgrounds are presented in Chapter 2. Chapter 3 discusses the adsorption of oxygen on Pt(111) at various temperatures and its role in the oxidation of carbon monoxide. Chapter 4 gives an atomic scale insight into the reaction between adsorbed oxygen and carbon monoxide for different ratios of oxygen and carbon monoxide pressures. In Chapter 5, the reaction between CO and oxygen on Pt(111) was used to register noise in tunneling current due to diffusion and recombination of molecules on the catalytically active surface, to draw conclusions on the most likely rate-limiting step in the process Show less
The notions of category and type are here studied through the lens of logical syntax: Aristotle's as well as Kant's categories through the traditional form of proposition `S is P', and modern... Show moreThe notions of category and type are here studied through the lens of logical syntax: Aristotle's as well as Kant's categories through the traditional form of proposition `S is P', and modern doctrines of type through the Fregean form of proposition `F(a)', function applied to argument. Topics covered include the conception of categories as highest genera; the parts of speech and their relation to categories; the attempt to derive categories from more fundamental notions; the notion of a range of significance; the notion of a type assignment; sortal concepts and the notions of identity and generality; and the distinction between formal and material categories. Show less
Spin-crossover compounds showing thermal hysteresis exhibit magnetic and colourmetric bistablility, which is of interest for a number of applications such as information storage and optical... Show moreSpin-crossover compounds showing thermal hysteresis exhibit magnetic and colourmetric bistablility, which is of interest for a number of applications such as information storage and optical displays. Mononuclear iron(II) complexes hold considerable potential in this field, and their cooperative properties may suffer less from size reduction effects than polymeric SCO materials because the coordination environment remains well defined throughout the material. In this thesis, 13 new mononuclear spin-transition materials based on the bapbpy scaffold are described. One of these compounds, [Fe(bbpya)(NCS)2], shows one of the highest transition temperatures (418 K) recorded among known mononuclear SCO complexes. Most interestingly, it keeps a large hysteresis cycle of 21 K in spite of its high transition temperature. Meanwhile, metal dilution study on [Fe(bapbpy)(NCS)2] clearly shows that the two steps and the hysteresis cycles of the SCO are two consequences of the same phenomenon: intermolecular interactions between spin-switching molecules. Finally, a new bapphen-based ligand bearing a 12-carbon alkyl chain at the back of the tetrapyridyl ligand was prepared, which allowed self-assembling the corresponding iron(II) complex on a highly oriented pyrolytic graphite (HOPG) surface. The stable and highly ordered 2D patterns observed by STM are promising for the future study of cooperative spin crossover at surfaces. Show less
Alzheimer's disease is manifested in amyloid fibril but caused by protofibril oligomers of A_ peptide and tau protein. I discovered a molecular mechanism which involves a new globular state of the... Show moreAlzheimer's disease is manifested in amyloid fibril but caused by protofibril oligomers of A_ peptide and tau protein. I discovered a molecular mechanism which involves a new globular state of the A_ peptide formed by protofibril oligomers, and from which fibrils can nucleate. Another striking finding in my thesis is to present new concept to inhibit amyloid fibrillation. For instance, natural factors found in vivo, such as ,lysozyme, insulin and spermine, and non-natural factors found in vitro, like gramicidin S, can interfere with the toxicity and fibrillation of A_. Show less
The research presented in the thesis describes the development and implementation of solution based NMR methods that provide 3D structural information on the protein-small molecule complexes. These... Show moreThe research presented in the thesis describes the development and implementation of solution based NMR methods that provide 3D structural information on the protein-small molecule complexes. These methods can be critical for structure based drug design and can be readily applied in the early stages of preclinical drug discovery and fragment based drug discovery Show less
Streptomyces are Gram-positive, soil dwelling bacteria that raised interest in the last 50 years for their high potential in antibiotic and protein production. Thanks to their saprophytic nature,... Show moreStreptomyces are Gram-positive, soil dwelling bacteria that raised interest in the last 50 years for their high potential in antibiotic and protein production. Thanks to their saprophytic nature, streptomycetes secrete a massive amount of industrial enzymes. They have a relatively low level of endogenous extracellular proteolytic activity when compared to other expression hosts (e.g. Bacillus), they are generally more suited to produce proteins encoded by high G+C actinomycete genes in their native form, coupled to efficient secretion so as to avoid that the proteins end up in inclusion bodies (often a problem when using e.g. E. coli) and making downstream processes easier. Despite their attractive potential, Streptomyces present several constraints which so far limit their application in industry. The first constraint is morphology: by growing as a network of hyphae, they produce dense pellets in liquid cultures that hold Streptomyces back from being one of the first choice cell factories in large scale fermentations. In addition, the limited availability of efficient expression systems for high-level transcription/translation and subsequent secretion is a further bottleneck. This thesis presents the work done to address these issues for the optimization of Streptomyces lividans for future industrial applications and enzyme production. Show less
By utilizing paramagnetic NMR techniques, the structure and dynamics of the P450cam system were investigated. The analysis of PCS and RDC illuminated the stereo-specific final complex of Pdx and... Show moreBy utilizing paramagnetic NMR techniques, the structure and dynamics of the P450cam system were investigated. The analysis of PCS and RDC illuminated the stereo-specific final complex of Pdx and P450cam, while the results of PRE demonstrated the presence of a transient encounter complex. Furthermore, the significant insights of the interaction in the interface were uncovered by X-ray crystallography. Currently, the nature of Pdx effector activity is under debate. Since paramagnetic NMR experiments are applicable to solution studies at ambient temperature, PCS, RDC and PRE methods can further resolve the molecular mechanism of P450cam in the future. Show less
Solid-state photochemically induced dynamic polarisation (photo-CIDNP) is one of the hyperpolarization techniques that tremendously enhances the sensitivity and selectivity of solid state NMR.... Show moreSolid-state photochemically induced dynamic polarisation (photo-CIDNP) is one of the hyperpolarization techniques that tremendously enhances the sensitivity and selectivity of solid state NMR. Photo-CIDNP MAS NMR studies on entire cells of heliobacteria Hb. mobilis in both anaerobic and aerobic forms are presented in Chapter 2. This chapter demonstrates that photo-CIDNP MAS NMR can be applied as an analytical tool directly on to cells and bacteria even if no further purification is known or possible. To improve the knowledge of the solid-state photo-CIDNP effect, field dependencies are measured over large ranges (Chapter 3). The electron spin density distribution in the 3P donor triplet state is constructed here using the analysis of differential relaxation mechanism and this stresses the versatility of photo-CIDNP MAS NMR as hyperpolarization method. Chapter 4 describes the first observation of photo-CIDNP MAS NM R in phototropin LOV1-C57S, overcoming an old limitation of this method to natural photosynthetic RCs. The first analytical studies on the LOV1 system in Chapter 5 provides the potential to develop photo-CIDNP MAS NMR into an enhancement method generally applicable to electron transfer proteins. In Chapter 6 this leads to a new paradigm, expecting plenty of photo-CIDNP hyperpolarization if the experiment is optimized for the LOV1 system. Show less
Cells express a large array of membrane receptors on their surface that function as a communication channel between the extra- and intracellular environment of the cell. Ligands for these receptors... Show moreCells express a large array of membrane receptors on their surface that function as a communication channel between the extra- and intracellular environment of the cell. Ligands for these receptors span a wide range of biomolecules, from proteins to carbohydrates to small molecules. Some receptors are continuously recycling between the membrane and the inside of a cell, whereas others are in a steady-state at the membrane and need ligand binding for their activation and subsequent internalization. Synthetic molecules that bind to these membrane receptors can be used to either modulate their function, or to target a reporter group (i.e. a fluorescent dye) and/or a bio-active compound (drug, protein) to cells that express this receptor, ensuring delivery to a specific cell-type. The research described in this Thesis combines synthetic and biochemical methodologies to create ligands that interact selectively with membrane receptors of the GPCR and lectin-binding families. Attachment of synthetic probes, proteins or cytostatic molecules to these ligands by a variety of chemical and enzymatic methods ensured their uptake exclusively into cells that expressed the receptor of interest. Visualization of this process was enabled by the incorporation of a fluorescent dye into the final constructs. Show less
This thesis may be regarded as a concept work, to see how feasible drug discovery approaches still are. For this, a strain collection was built up consisting of actinomycetes from soil in the... Show moreThis thesis may be regarded as a concept work, to see how feasible drug discovery approaches still are. For this, a strain collection was built up consisting of actinomycetes from soil in the Qinling and Himalaya mountains, which were subsequently tested for antibiotic production against multi-drug resistant clinical isolates. This resulted in close to 100 strains that showed strong antimicrobial activity, which were then analyzed in more detail. Two of the strains were subjected to extensive NMR-based metabolomics assisted by mass spectrometry, and several known and also novel antimicrobial compounds were elucidated. Finally, we also focused on the antibiotic activity of volatile organic compounds (VOCs) Show less
