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DEVELOPMENT OF A MINIMAL POLYMER MODEL FOR THE DESCRIPTION OF BETA HAIRPIN FORMATIONMilam, Kenneth E. 05 October 2006 (has links)
No description available.
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Minimal model for the secondary structures and conformational conversions in proteinsImamura, Hideo January 2005 (has links)
Better understanding of protein folding process can provide physical insights on the function of proteins and makes it possible to benefit from genetic information accumulated so far. Protein folding process normally takes place in less than seconds but even seconds are beyond reach of current computational power for simulations on a system of all-atom detail. Hence, to model and explore protein folding process it is crucial to construct a proper model that can adequately describe the physical process and mechanism for the relevant time scale. We discuss the reduced off-lattice model that can express <em>α</em>-helix and <em>β</em>-hairpin conformations defined solely by a given sequence in order to investigate a protein folding mechanism of conformations such as a <em>β</em>-hairpin and also to investigate conformational conversions in proteins. The first two chapters introduce and review essential concepts in protein folding modelling physical interaction in proteins, various simple models, and also review computational methods, in particular, the Metropolis Monte Carlo method, its dynamic interpretation and thermodynamic Monte Carlo algorithms. Chapter 3 describes the minimalist model that represents both <em>α</em>-helix and <em>β</em>-sheet conformations using simple potentials. The native conformation can be specified by the sequence without particular conformational biases to a reference state. In Chapter 4, the model is used to investigate the folding mechanism of <em>β</em>-hairpins exhaustively using the dynamic Monte Carlo and a thermodynamic Monte Carlo method an effcient combination of the multicanonical Monte Carlo and the weighted histogram analysis method. We show that the major folding pathways and folding rate depend on the location of a hydrophobic. The conformational conversions between <em>α</em>-helix and <em>β</em>-sheet conformations are examined in Chapter 5 and 6. First, the conformational conversion due to mutation in a non-hydrophobic system and then the conformational conversion due to mutation with a hydrophobic pair at a different position at various temperatures are examined.
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Minimal model for the secondary structures and conformational conversions in proteinsImamura, Hideo January 2005 (has links)
Better understanding of protein folding process can provide physical insights on the function of proteins and makes it possible to benefit from genetic information accumulated so far. Protein folding process normally takes place in less than seconds but even seconds are beyond reach of current computational power for simulations on a system of all-atom detail. Hence, to model and explore protein folding process it is crucial to construct a proper model that can adequately describe the physical process and mechanism for the relevant time scale. We discuss the reduced off-lattice model that can express <em>α</em>-helix and <em>β</em>-hairpin conformations defined solely by a given sequence in order to investigate a protein folding mechanism of conformations such as a <em>β</em>-hairpin and also to investigate conformational conversions in proteins. The first two chapters introduce and review essential concepts in protein folding modelling physical interaction in proteins, various simple models, and also review computational methods, in particular, the Metropolis Monte Carlo method, its dynamic interpretation and thermodynamic Monte Carlo algorithms. Chapter 3 describes the minimalist model that represents both <em>α</em>-helix and <em>β</em>-sheet conformations using simple potentials. The native conformation can be specified by the sequence without particular conformational biases to a reference state. In Chapter 4, the model is used to investigate the folding mechanism of <em>β</em>-hairpins exhaustively using the dynamic Monte Carlo and a thermodynamic Monte Carlo method an effcient combination of the multicanonical Monte Carlo and the weighted histogram analysis method. We show that the major folding pathways and folding rate depend on the location of a hydrophobic. The conformational conversions between <em>α</em>-helix and <em>β</em>-sheet conformations are examined in Chapter 5 and 6. First, the conformational conversion due to mutation in a non-hydrophobic system and then the conformational conversion due to mutation with a hydrophobic pair at a different position at various temperatures are examined.
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A Molecular Mechanics Knowledge Base Applied to Template Based Structure PredictionQu, Xiaotao 2009 December 1900 (has links)
Predicting protein structure using its primary sequence has always been a
challenging topic in biochemistry. Although it seems as simple as finding the minimal
energy conformation, it has been quite difficult to provide an accurate yet reliable
solution for the problem. On the one hand, the lack of understanding of the hydrophobic
effect as well as the relationship between different stabilizing forces, such as
hydrophobic interaction, hydrogen bonding and electronic static interaction prevent the
scientist from developing potential functions to estimate free energy. On the other hand,
structure databases are limited with redundant structures, which represent a noncontinuous,
sparsely-sampled conformational space, and preventing the development of
a method suitable for high-resolution, high-accuracy structure prediction that can be
applied for functional annotation of an unknown protein sequence. Thus, in this study,
we use molecular dynamics simulation as a tool to sample conformational space.
Structures were generated with physically realistic conformations that represented the
properties of ensembles of native structures. First, we focused our study on the relationship among different factors that stabilize protein structure. Using a wellcharacterized
mutation system of the B-hairpin, a fundamental building block of protein,
we were able to identify the effect of terminal ion-pairs (salt-bridges) on the stability of
the beta-hairpin, and its relationship with hydrophobic interactions and hydrogen bonds. In
the same study, we also correlated our theoretical simulations qualitatively with
experimental results. Such analysis provides us a better understanding of beta-hairpin
stability and helps us to improve the protein engineering method to design more stable
hairpins. Second, with large-scale simulations of different representative protein folds,
we were able to conduct a fine-grained analysis by sampling the continuous
conformational space to characterize the relationship among backbone conformation,
side-chain conformation and side-chain packing. Such information is valuable for
improving high-resolution structure prediction. Last, with this information, we
developed a new prediction algorithm using packing information derived from the
conserved relative packing groups. Based on its performance in CASP7, we were able to
draw the conclusion that our simulated dataset as well as our packing-oriented prediction method are useful for template based structure prediction.
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Mimes synthétiques de feuillets bêta : conception, synthèse et évaluation de leur capacité à moduler l'agrégation du peptide bêta-amyloïde 1-42. / Synthetic mimics of beta-sheets : design, synthesis and evaluation of their ability to modulate the aggregation of the beta-amyloid 1-42 peptide.Tonali, Nicolo 24 November 2016 (has links)
La maladie d'Alzheimer (MA) est une maladie neurodégénérative liée à l’oligomérisation et à la fibrillation du peptide bêta amyloïde, avec Abêta 1-42 étant le plus agrégeant et neurotoxique. La cause exacte de la maladie d'Alzheimer n’est pas encore connue et donc il n'y a pas de traitement efficace contre cette maladie.Une stratégie prometteuse pourrait être l'inhibition de l'oligomérisation de monomères solubles d'Abêta;, en stabilisant la conformation non structurée native du peptide, à travers l’utilisation de composés capables d'empêcher la formation de feuillets bêta. En effet, les peu d'études structurales des espèces oligomériques et des fibrilles ont révélé que l'agrégation implique des structures en feuillet bêta.De nombreuses petites molécules ont été proposées pour leur capacité à inhiber ou moduler l'agrégation de Abêta 1-42 et sa toxicité. Cependant, le processus d'agrégation est très complexe et difficile à contrôler. Des études récentes indiquent que les oligomères solubles transitoires précédant la formation de fibrilles sont les espèces les plus toxiques. Ainsi, le développement d'inhibiteurs ciblant à la fois l’oligomérisation et la fibrillation reste difficile en dépit de son importance thérapeutique. Les peptides sont des alternatives raisonnables aux autres produits pharmaceutiques chimiques. En particulier, l'inhibition de l'agrégation de Abêta; a été ciblée en utilisant des éléments d'auto-reconnaissance (SRE), qui sont des séquences d'acides aminés clés impliqués dans les différentes espèces agrégées. À notre connaissance, l'utilisation de petites "bêta-hairpins" acycliques a été très rarement explorée comme ligands de feuillets-bêta et comme inhibiteurs de l'agrégation.Comme l’agrégation de Abêta est un processus dynamique et complexe, nous avons supposé que les "bêta-hairpins" flexibles pourraient mieux s'adapter dans l'interaction avec les différentes conformations de Abêta 1-42 présents pendant le processus d'agrégation, et en particulier dans les premiers stades de l'oligomérisation. Nous avons conçu des mimes de feuillets bêta acycliques basés sur un squelette semi-rigide de type pipéridine-pyrrolidine comme inducteur flexible de coude bêta, et sur différents SREs de Abêta 1-42. Le choix des SREs a été basée sur les structures d'oligomères et fibrilles.La capacité de tous les composés a été évaluée par spectroscopie de fluorescence à la thioflavine-T pour déterminer l'activité inhibitrice. Les résultats obtenus ont été complétés par microscopie à transmission électronique. Les composés les plus prometteurs ont également été étudiés par électrophorèse capillaire (EC) pour suivre les étapes très précoces du processus d'oligomérisation. Les meilleurs inhibiteurs ont été étudiés afin de déterminer leur capacité à réduire la toxicité de Abêta 1-42 sur des cellules de neuroblastome SH-SY5Y.Nous rapportons également dans cette thèse les études conformationnelles, effectuées par RMN et réalisées pour étudier et confirmer la capacité de composés de se structurer en solution comme des "bêta-hairpins".Enfin, nous avons développé une voie de synthèse pour obtenir de nouvelles chaînes peptidomimétiques composées par des résidus aza-aminoacides. Dans la littérature, seules des séquences peptidiques comportant un seul résidu aza-aminoacide au milieu, sont connues, mais les propriétés de liaison hydrogène d’un 2:1 [aza/alpha]-tripeptide ne sont pas encore, à notre connaissance, étudiées ni exploitées dans la conception d’inhibiteurs des interactions protéine-protéine. Nous présentons dans cette thèse les études conformationelles réalisées par RMN, cristallographie aux rayons X et modélisation moléculaire.On peut conclure que les éléments structurels décrits dans cette thèse fournissent des indications précieuses dans la compréhension du processus d'agrégation du peptide Abêta 1-42 et dans la conception de nouveaux " bêta-hairpins" acycliques ciblant des protéines amyloïdes. / Amyloidosis is the generic word to name a group of diseases that are caused by the misfolding and extracellular accumulation of various proteins. Alzheimer’s disease (AD) is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides, with Aβ 1-42 being the most aggregative and neurotoxic one. To date, the exactly cause of the Alzheimer's disease is not still known and so there is no effective treatment of the disease.An attractive strategy for treating AD could be the inhibition of the oligomerization of soluble Aβ monomers, by stabilizing the native unstructured conformation of the peptide, using compounds able to prevent the formation of β-sheets. Indeed, few structural studies of oligomeric species and fibrils revealed that the aggregation involves β-sheet structures.A large number of small molecules have been proposed for their ability to inhibit or modulate Aβ1-42 aggregation and toxicity. However, the aggregation process is highly complex, and extremely difficult to control. Recent studies indicate that soluble transient oligomers preceding fibril formation are highly toxic species. Thus, the development of inhibitors targeting both oligomerization and fibrillization remains challenging despite its therapeutic significance. Peptides are today reasonable alternatives to small molecule pharmaceuticals. In particular, inhibition of Aβ-aggregation has been targeted using self-recognition elements (SREs), which are key amino acid sequences involved in the different aggregated species. To our knowledge, the use of small acyclic β-hairpins has been very rarely explored as β-sheet binders and inhibitors of aggregation.As Aβ-aggregation is a dynamic and complex process, we hypothesized that flexible β-hairpins could adapt themselves in the interaction with the different Aβ1-42 conformations present during the aggregation process, and in particular in the early stages of oligomerization. We designed acyclic β-hairpin mimics based on a piperidine-pyrrolidine semi-rigid scaffold developed recently as a flexible β-turn inducer, and on different SREs of Aβ1-42. The choice of the SREs was based on oligomer and fibril structures.The ability of all compounds to influence the Aβ 1-42 fibrillization process was evaluated by thioflavin-T fluorescence spectroscopy, used as an evaluation tool to define the inhibitory activity. The obtained results were successively supplemented by transmission electron microscopy. The most promising compounds were also studied by Capillary Electrophoresis (CE) using a method we recently proposed to monitor the very early steps of the oligomerization process overtime. The best inhibitors were investigated to determine their ability to reduce the toxicity of aggregated Aβ1-42 to SH-SY5Y neuroblastoma cells.Together with the evaluation of these molecules, we report in this thesis the conformational studies performed by NMR. These structure investigations were performed to investigate and confirm the β-hairpin conformational preference of the compounds in solution.Finally, we performed a practical synthetic pathway to obtain new peptidomimetic chains composed by aza-amino acid residues. In the literature only peptide sequence, with just one aza-amino acid residue in the middle, are known, but the hydrogen-bonding properties of 2:1 [Aza/α]-tripeptides have not yet, to our knowledge, been exploited in the design of the inhibition of protein-protein interactions. We present in this thesis the conformational studies of the 2:1 [Aza/α]-tripeptide sequence by NMR analyses, X-ray crystallography and molecular modelling.In conclusion, the structural elements made in this thesis provide valuable insights in the understanding of the aggregation process of Aβ 1-42 peptide and to explore the design of novel acyclic β-hairpin targeting amyloid-forming proteins.
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Structural Characterization Of Protein Folding IntermediatesBhattacharjya, Surajit 10 1900 (has links) (PDF)
No description available.
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Optimising His-tags for purification and phasing / Optimierte His-tags für Aufreinigung und PhasierungGroβe, Christian 05 October 2010 (has links)
No description available.
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X-ray Crystallographic Studies Of Designed Peptides : Characterization Of Helices And B-HairpinsAravinda, S 02 1900 (has links) (PDF)
No description available.
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