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1
Baylies, Christian John. "Synthesis of multidentate pyridyl-thiazole ligands and ligand recognition studies." Thesis, University of Huddersfield, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399824.
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Hughes, P. J. "Multivalent ligand recognition by pentraxins." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1473766/.
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The pentraxins, serum amyloid P component (SAP) and C-reactive protein (CRP) are target proteins for the development of treatments for amyloidosis and ischaemic injury, respectively, in humans. This study reports the first multivalent ligands capable of targeting all five SAP binding sites simultaneously. Ligands presenting five or ten D-proline headgroups and composed of five peptideglycol linkers emanating from ε-N-substituted lysine residues on a central cyclic peptide core were synthesised by solid phase peptide synthesis. The sub-nanomolar, ~250pM, binding affinity approximated by Isothermal Titration Calorimetry (ITC) for one decavalent ligand is the strongest affinity for an SAP binding ligand currently known and stronger than the affinity of SAP binding to amyloid deposits. X-ray crystallography and mass spectrometry shows the decavalent ligands noncovalently cross-linking two SAP pentamers, in the same manner observed for lead drug candidate CPHPC, but with increased affinity. In addition, the binding of SAP with N-acetyl D-proline has been investigated by x-ray crystallography. Using a 1.5Å resolution structure the exact interaction of the headgroup used in CPHPC, penta- and decavalent ligands, was investigated. The results show potential for an electrostatic interaction between the carbonyl oxygen of acetyl from the ligand and the side chain amide of Gln148, which has not previously been considered. Applications of multivalent binding are still emerging; in this study, bivalent ligand BPC8 was used as an additive to crystallise CRP from the Rat (rCRP) in non-covalently cross-linked decameric complexes. Previous x-ray crystallography studies have failed due to extreme radiation sensitivity of the crystals produced. This problem has been overcome with a complete dataset obtained from a single crystal at 3.2Å. No inter-protein contacts are seen between pentamers in the decamer complex, therefore the use of bivalent ligands has facilitated the observed crystal packing. Multivalent ligands are suggested as tools for overcoming difficult crystallisation issues.
3
McCleverty, Clare. "Structure-function studies of integrin-ligand recognition." Thesis, University of Leicester, 2001. http://hdl.handle.net/2381/29664.
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Integrins are a large family of αβ heterodimeric cell surface receptors that interact with the extracellular matrix and/or counter-receptors on other cells. These interactions control the adhesion and migration of cells as well as regulating numerous signal transduction pathways. Integrins exist in low and high affinity states, subject to allosteric regulation. Integrin-ligand recognition is divalent cation-dependent and mediated by the α subunit N-terminal repeats, the β subunit I domain and in certain integrins, the α subunit I domain. Two competing models based upon structure predictions, the β-propeller and EF-hand-like models, were tested to determine which model represents the structural components of the ligand binding α subunit N-terminal repeats. Recombinant fragments of α4 repeats IV-V, VI-VII and IV-VII, corresponding to the EF-hand-like model, were insoluble, thus preventing further analysis. A recombinant fragment of all seven α4 repeats contains a predominant secondary structure content of anti-parallel β-sheet, compatible with the β-propeller model. The interactions of the αM I domain with fragment D from fibrinogen and the extracellular domains of ICAM-1 were studied using surface plasmon resonance. Optimal binding conditions and equilibrium dissociation constants were established for these interactions. Co-crystallisation studies were pursued with the αM I domain and its ligands, fragment D and ICAM-1, but a co-crystal was not obtained due to the presence of a subpopulation of low affinity I domain molecules. Disulphide bonds were then introduced to lock the αM I domain in the open and closed conformations, corresponding to the high and low affinity states, respectively. Equilibrium dissociation constants for the open and closed mutants reveal a marked increase and decrease in ligand binding affinity, respectively. Stabilisation of the closed mutant via a disulphide bond is verified in the crystal structure. The affinity state of both mutants is fully reversible by reduction of the disulphide bond. These mutants provide useful tools for future studies to understand integrin allostery and will simplify ligand binding studies in the isolated I domain and intact receptor.
4
Roy, Julie. "Ligand recognition by the major urinary protein." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/27908/.
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Molecular Dynamics (MD) and Quartz Crystal Microbalance (QCM) techniques can provide unique insights into what drives protein-ligand association. The major urinary protein (MUP) binds small ligands in a deeply buried hydrophobic pocket. Detailed calorimetric studies have shown that ligand binding is driven by enthalpic effects, not entropic effects [1]. Previous studies have shown that this is due to 'dewetting' of the binding site cavity even in the absence of ligands, and have also characterised the complex changes in molecular flexibility that accompany ligand binding-features that may be correlated with NMR data [2]. Recent MD revealed the hydration effects of apo-MUP and also shown where certain regions of MUP become more flexible upon ligand binding. They have also shown a water molecule remains close to the tyrosine in the binding pocket [2]. In our current MD studies and OCM experiments we have used wild type and 2 different mutants of MUP to study the binding effects of the ligand IBM. The first mutant has an OH group removed from the binding site of MUP (i.e. tyrosine to phenylalanine (Y120F)). The second mutant has an extra OH group in the binding site (i.e. alanine to serine (A103S)). For all three systems the hydration and flexibility upon ligand binding has been analysed. The hydration analysis from MD reveal (from radial distribution curves and hydration density maps) there is a small density of water that remains even without the presence of the ligand for the WT MUP whereas a larger density of water remains in the binding cavity of the A103S hydrophilic MUP simulation. The results are based on the average structure generated from the 1 mus simulations. The Y120F MUP simulations reveal that there is no water molecules present in the binding cavity. However, as protein molecules are very dynamic in nature, water molecules are observed to hop in and out of the binding pockets for both mutant MUP (but not WT MUP) simulations over the 1 mus simulations. On the other hand the experimental QCM results reveal that on ligand binding no water loss is observed for Y120F mutant MUP whereas A103S and WT MUP have about 2 water molecules which are lost in the binding cavity. The flexibility results from the MD simulations reveal that WT MUP have some residues which increase in flexibility whilst other residues which decrease in flexibility on ligand binding. However, the Y120F hydrophobic MUP show an overall decrease in flexibility whereas the A103S MUP shows an overall increase in flexibility on ligand binding. In contrast the experimental OCM and AFM results reveal that there is an increase in flexibility on ligand binding to all 3 different types of MUP molecules. The experimental and the simulation data have shown a variation in results but it is to be noted that the results cannot be directly compared as the analytical experiments are a surface based techniques whereas the MD simulations do not involve a surface. However, the contrast observed between computer simulation and experiments has revealed important information on the ligand binding effects on MUP. [1] Bingham, R.J., J.B.C. Findlay, S.Y. Hsieh, A.P. Kalverda, A. Kjeliberg, C. Perazzolo, S.E.V. Phillips, K. Seshadri, C.H. Trinh, W. B. TurnbulI, G. Bodenhausen, and S.W. Homans. 2004. Thermodynamics of binding of 2-methoxy-3-lsopropylpyrazlne and 2- methoxy-3-lsobutylpyrazine to the major urinary protein. J. Am. Chem. Soc. 126:1675-1681. [2] Barratt, E., R.J. Bingham. D.J. Warner, C.A. Laughton, S.E.V. Phillips, and S.W. Homans. 2005. Van der Waals interactions dominate ligand-protein association in a protein binding site occluded from solvent water. J. Am. Chem. Soc. 127:11827-11834.
5
Croft, Edward. "Computational analyses of protein-ligand interactions." Thesis, University of York, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265562.
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Lind, Ulrika. "Functional analysis of ligand recognition by the glucocorticoid receptor /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4116-5/.
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Hatherley, Deborah. "Structural basis of ligand recognition by Myeloid Paired Receptors." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543484.
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Costanzi, Elisa. "Structural analysis of molecular recognition and ligand association processes." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3421838.
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Molecular recognition is a fundamental step in essentially any biochemical process. Detailed structural knowledge is crucial to have a better understanding of the processes in which the two interacting molecular partners are involved and can be exploited in several applied fields such as supramolecular design of new molecular assemblies, rational drug design, and enzyme engineering. In the context of molecular recognition, I have investigated (mainly by single crystal x-ray crystallography) some relevant protein-protein and protein-ligand systems in order to gain detailed structural insights on the interactions involved, at atomic level.
First, the STAS domain of prestin, an anion-dependent motor protein, and its interaction with monovalent anions and with calmodulin.
Second, the interaction between protein kinases (CDK2 and CK2) and BCLXL, and inhibitors, for the rational design of specific drugs targeting these proteins involved in different types of cancer.<br>Il riconoscimento molecolare è uno step fondamentale nei processi biochimici. Una conoscenza strutturale dettagliata è cruciale per capire meglio i processi in cui sono coinvolti due partner molecolari interagenti e può essere sfruttata in vari campi come il disegno di nuovi assemblamenti sopramolecolari, il disegno razionale di farmaci e l’ingegnerizzazione di enzimi. In questo contesto, ho investigato (prevalentemente tramite cristallografia a raggi x su cristallo singolo) alcuni sistemi proteina-proteina
e proteina-ligando per ottenere dettagli strutturali delle interazioni coinvolte, a livello atomico.
In primis, il dominio STAS di prestina, una proteina motrice anionidipendente, e la sua interazione con anioni monovalenti e con calmodulina.
Poi, l’interazione tra protein chinasi (CDK2 e CK2) e BCL-XL, e inibitori, per il disegno razionale di farmaci specifici nel colpire queste proteine coinvolte in vari tipi di cancro.
9
Repicky, Sarah Elizabeth. "The Structural Basis for Ligand Recognition by Mouse Odorant Receptors." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/91.
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Mammalian odorant receptors (ORs) are Class I G-protein coupled receptors (GPCRs) located within the nasal epithelium. Odorant receptors interact with Galpha olfactory, a Galpha S type G-protein. Activated Galpha olfactory stimulates adenylate cyclase and the resulting increase in cAMP concentration opens cyclic nucleotide gated channels allowing Ca2+ to enter the cell. The increased Ca2+ then activates a Ca2+ activated Cl- channel which further depolarizes the cell. This depolarization initiates an action potential that reaches the axon of the olfactory sensory neuron located in the main olfactory bulb. Information from the main olfactory bulb is then transmitted to higher regions of the brain. Olfactory information is initially coded through the interaction of odorant molecules with hundreds of distinct ORs, but difficulty in exogenous expression of odorant receptors has delayed the identification of ligands for individual ORs. However, expression of mouse odorant receptors in Xenopus laevis oocytes allows for a systematic screening for potential ligands, as well as for efficient study of the structure-function relationship of the receptors and their ligands. My screening of odorant receptors using Xenopus oocytes included the coexpression of a signal transduction system and the use of robotic two-electrode voltage clamp electrophysiology. In this study, I investigated the structural basis for ligand recognition in mouse odorant receptors. First, I expanded the molecular receptor ranges of seven Class I odorant receptors. By use of a high throughput assay, I was able to expand upon current knowledge in the field for the mouse odorant receptors 23-1, 31-4, 32-11, 40-4, 42-1, 42-2 and 42-3. I then examined one receptor (MOR23-1) in more detail. I used the substituted cysteine accessibility method to identify residues within transmembrane domain five of this receptor that are accessible from the extracellular space. These residues may line the ligand binding site or the ligand access pathway. Conventional mutations of A205 caused little alteration in the molecular receptive range of the receptor, suggesting that this residue may not play a significant role in ligand interaction within the binding pocket. Mutagenesis of G111, a residue within transmembrane domain three caused significant shifts in the molecular receptive range of the receptor, but the location of this residue within the binding pocket could not be confirmed by the substituted cysteine method. Previous reports had suggested significant similarity between the molecular receptive ranges of the seven mouse odorant receptors that I used in my research. By expanding upon the known aliphatic ligands for each receptor identified new ligands for each receptor, I was able to show that the molecular receptive ranges of these receptors are in fact distinct. The experimental identification of residues located within the binding pocket on transmembrane five of mouse odorant receptor 23-1 provides an improved understanding of ligand recognition by this receptor class and will aid in better computer modeling of these receptors. This increased accuracy of the computer models of these basic Class I GPCRs may aid in future drug discoveries. Since GPCRs constitute a significant fraction of current drug targets, understanding the mechanism of ligand interactions with mouse odorant receptors may aid in the development of more efficacious compounds in the treatment of many common ailments.
10
Śledź, Paweł. "Novel biophysical approaches to the study of protein-ligand recognition." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610024.
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Han, Yaohua. "Quantum Chemical Study of Molecular Recognition in Protein-Ligand Complexes." University of Toledo / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1373313907.
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Salmaso, Veronica. "Exploring protein flexibility during docking to investigate ligand-target recognition." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3421817.
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Ligand-protein binding models have experienced an evolution during time: from the lock-key model to induced-fit and conformational selection, the role of protein flexibility has become more and more relevant. Understanding binding mechanism is of great importance in drug-discovery, because it could help to rationalize the activity of known binders and to optimize them. The application of computational techniques to drug-discovery has been reported since the 1980s, with the advent computer-aided drug design. During the years several techniques have been developed to address the protein flexibility issue.
The present work proposes a strategy to consider protein structure variability in molecular docking, through a ligand-based/structure-based integrated approach and through the development of a fully automatic cross-docking benchmark pipeline.
Moreover, a full exploration of protein flexibility during the binding process is proposed through the Supervised Molecular Dynamics. The application of a tabu-like algorithm to classical molecular dynamics accelerates the binding process from the micro-millisecond to the nanosecond timescales. In the present work, an implementation of this algorithm has been performed to study peptide-protein recognition processes.<br>I modelli di riconoscimento ligando-proteina si sono evoluti nel corso degli anni: dal modello chiave-serratura a quello di fit-indotto e selezione conformazionale, il ruolo della flessibilità proteica è diventato via via più importante. Capire il meccanismo di riconoscimento è di grande importanza nella progettazione di nuovi farmaci, perchè può dare la possibilità di razionalizzare l’attività di ligandi noti e di ottimizzarli. L’applicazione di tecniche computazionali alla scoperta di nuovi farmaci risale agli anni ‘80, con l’avvento del cosiddetto “Computer-Aided Drug Design”, o, tradotto, progettazione di farmaci aiutata dal computer. Negli anni sono state sviluppate molte tecniche che hanno affrontato il problema della flessibilità proteica.
Questo lavoro propone una strategia per considerare la variabilità delle strutture proteiche nel docking, attraverso un approccio combinato ligand-based/structure-based e attraverso lo sviluppo di una procedura completamente automatizzata di docking incrociato.
In aggiunta, viene proposta una piena esplorazione della flessibilità proteica durante il processo di legame attraverso la Dinamica Molecolare Supervisionata. L’applicazione di un algoritmo simil-tabu alla dinamica molecolare classica accelera il processo di riconoscimento dalla scala dei micro-millisecondi a quella dei nanosecondi. Nel presente lavoro è stata fatta un’implementazione di questa algoritmica per studiare il processo di riconoscimento peptide-proteina.
13
Orro, Graña Adolfo. "Examination of the role of binding site water molecules in molecular recognition." Thesis, SciLifeLab Stockholm, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-200164.
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A set of algorithms were designed, implemented and evaluated in order to, first, identifyclusters of conserved waters in binding pockets, i.e. hydration sites. Then, their contributionto the free energy of binding in a ligand-protein association was quantified by calculatingtheir enthalpy and entropy. The information obtained by using these algorithms couldcontribute to the development of new drugs by generating new ligands that target specifichigh-energy, unfavorable waters. Evaluation tests show that our algorithms can indeedprovide relevant data about how hydration sites influence ligand-protein binding.
14
Cuzzolin, Alberto. "Novel in silico approaches to depict the protein-ligand recognition events." Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424818.
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The discovery and commercialization of a new drug is a long and expensive process. Such process is divided into different phases during which the phisico-chemical and therapeutic properties of the compounds are determined. In particular, the aim of the first phase is to verify whether the compound recognises and interacts efficiently with the target protein.
In the last decade, several computational tools have been developed and used to support experimentalists. For this purpose, the scientist have to deal with high complex systems that are difficult to study in whole; thus, the methods and algorithms developers have to strongly simplify the system treatment. Moreover, the time required to obtain the results depends on the computational resources (hardware) available. Fortunately, the technological progress have increased the computing power at low cost, resulting in new and more complex techniques development.
During this Ph.D. project we were focused on the development and even the improvement of in silico methods, which allowed to answer certain questions by saving time and money. Furthermore, these methods were implemented in software presenting a Graphical Unit Interface (GUI) with the aim to enhance the user-friendliness.
The computational techniques often require a high understanding of the methodology theoretical aspects and also a good informatics proficiency, like different type files handling and hardware management. For this reason, our developed software were organized as pipelines to automatize the entire process and to make this tools useful also for non-expert users.
Finally, these methodologies were applied in several research projects demonstrating their usefulness by elucidating, for the first time, interesting aspects of the ligand-protein recognition pathway.<br>La scoperta e la commercializzazione di un nuovo farmaco è un processo lungo e dispendioso, che si articola in diverse fasi durante le quali vengono determinate le proprietà fisiche, chimiche e terapeutiche dei composti investigati. In particolare, nella prima fase di questo processo si cerca di verificare che il composto riconosca e interagisca efficacemente con la proteina bersaglio.
A tale scopo, negli ultimi decenni numerosi strumenti computazionali sono stati sviluppati e utilizzati per supportare i ricercatori che si adoperano nella parte sperimentale. I problemi affrontati presentano un alto livello di complessità, che sarebbero difficili da studiare in toto, perciò gli sviluppatori di metodi e algoritmi devono necessariamente adottare notevoli semplificazioni. Inoltre, le risorse di calcolo (hardware) determinano le tempistiche con le quali è possibile ottenere il risultato richiesto. In tal senso, lo sviluppo tecnologico ha portato a un importante aumento della potenza di calcolo a costi accessibili, stimolando l’interesse per lo sviluppo di tecniche sempre più complesse.
Durante questo progetto di dottorato ci si è focalizzati sullo sviluppo e il miglioramento di metodi in silico, che permettono di rispondere ad alcuni interrogativei a costi e tempistiche di molto ridotte.
Inoltre, tali metodi sono stati implementati in software dotati di interfaccia grafica (GUI) al fine di poter aiutare l’utente nel loro utilizzo.
Le tecniche computazionali spesso richiedono un’elevata conoscenza teorica delle metodologie e anche una certa competenza informatica, come la gestione di diversi tipologie di file e delle risorse hardware da impiegare. Per questo motivo i software da noi sviluppati sono stati organizzati in pipelines, in modo da automatizzare l’intero processo e rendere questi strumenti fruibili anhce a persone non esperte.
Infine, l’utilità di queste nuove metodologie è stata comprovata in progetti in cui questi strumenti hanno permesso di delucidare aspetti interessanti e fino ad ora non ancora accessibili nell’ambito del riconoscimento proteina-ligando.
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Lacey, Katie. "Regulation of ligand recognition and endocytosis by the LOX-1 scavenger receptor." Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589025.
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Lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that binds a wide range of ligands including oxidised low-density lipoprotein (OxLDL). LOX-1-mediated recognition of OxLDL can cause endothelial dysfunction and apoptosis. LOX-1 is implicated in foam cell formation and atherosclerotic plaque initiation and progression. The C-type lectin-like domain of LOX-1 binds OxLDL but the molecular basis for this recognition is unclear. Glycosidase or protease-mediated removal of exposed N-linked carbohydrates or protein epitopes on OxLDL led to the conclusion that LOX-1 recognises carbohydrates but not protein determinants on OxLDL. We hypothesised that the identification of such glycans would enable us to target the LOX-1-0xLDL interaction. Screening of a glycan array using recombinant LOX-1 identified GaINAcα1-3Galβ (carbohydrate 1) and Galα1-3(Galα1-4)Galβ1-4GlcNAcβ (carbohydrate 2) as potential LOX-1 ligands. Carbohydrate 1 was unable to block the interaction but 10 mM carbohydrate 2 almost completely abolished OxLDL binding. A simpler carbohydrate: Galα1-3(Galα1-4)Galβ-pMP (carbohydrate 3) was tested and showed improved blocking capability. Carbohydrate 3 administration to ApoE-/- transgenic mice fed a fat-rich diet showed decreased incidence of arterial atherosclerosis in comparison to controls. LOX-1 mediates endocytosis of OxLDL, in a clathrin- and AP-2-independent but dynamin-2-dependent manner and is reliant upon a novel DOL endocytic motif. Yeast-based genetic screens to identify cytosolic factors that bound wild-type (DOL) but not mutant (DAL) LOX-1 endocytic motifs, identified components of the AP-4 adaptor complex. Knockdown of the AP-4E subunit in epithelial cells expressing LOX-1, resulted in a significant decrease in LOX-1-mediated OxLDL internalisation. LOX-1 endocytosis also appears to be an actin-dependent process involving plasma membrane ruffles possibly regulated by the Rho Kinase, ROCK. Pharmacological inhibition of ROCK caused a significant decrease in LOX-1- mediated OxLDL endocytosis. This work has shed new light into the mechanisms regulating LOX-1-mediated ligand binding and endocytosis and has identified soluble inhibitors that block this interaction and are potential atherosclerosis therapeutics.
16
Yang, Hui. "Theoretical Studies of Molecular Recognition in Protein-Ligand and Protein-Protein Complexes." University of Toledo / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1282339026.
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Montalvo, Acosta Joel José. "Computational approaches to molecular recognition : from host-guest to protein-ligand binding." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAF051/document.
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La reconnaissance moléculaire est un problème très intéressant et surtout un défi actuel pour la chimie biophysique. Avoir des prévisions fiables sur la reconnaissance spécifique entre les molécules est hautement prioritaire, car il fournira un aperçu des problèmes fondamentaux et suscitera des applications technologiques pertinentes. La thèse présentée ici est centrée sur une analyse quantitatif de la reconnaissance moléculaire en solution pour la liaison l'hôte-invité, la liaison protéine-ligand et la catalyse. Le cadre de la mécanique statistique utilisé pour décrire l'état de la technique de liaison récepteur-ligand est un point d'inflexion pour le développement de nouvelles méthodes améliorées. En fait, un modèle très performant et précis a été obtenu pour l'analyse de la liaison hôte-invité. Enfin, les modèles présentés ont été utilisés comme outils prédictifs fiables pour la découverte de nouvelles entités chimiques destinées à améliorer la catalyse en solution<br>Molecular recognition is a very interesting problem, and foremost, a current challenge for biophysical chemistry. Having reliable predictions on the specific recognition between molecules is highly priority as it will provide an insight of fundamental problems and will raise relevant technological applications. The dissertation presented here is centered on a quantitative analysis of molecular recognition in solution for host-guest, protein-ligand binding and catalysis. The statistical mechanics framework used to describe the state-of-the-art for receptor-ligand binding is an inflection point for the developing of new improved and methods. In fact, a highly performanced and accurate model was obtained for the analysis of host-guest binding. Finally, the presented models were used as a reliable predictive tools for discovering new chemical entities for enhance catalysis in solution
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Su, Ruey-Chyi. "Major histocompatibility complex class I as a ligand for natural killer cell recognition." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0020/NQ53789.pdf.
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Mullin, Nicholas Paul. "Characterisation of ligand-binding to a carbohydrate-recognition domain of the macrophage mannose receptor." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320620.
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Tadayon, Roya [Verfasser], and Oliver [Akademischer Betreuer] Einsle. "Resolving the ligand-binding to pattern recognition receptor for advanced glycation end products (RAGE)." Freiburg : Universität, 2016. http://d-nb.info/115012427X/34.
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Deganutti, Giuseppe. "Ligand-receptor recognition events decoded at molecular scale by means of molecular dynamics simulations." Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3421924.
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During the last decades, the technological evolution has been very fast and has paved the way to a wide set of theoretical approaches able to support and stimulate the experimental component of biological sciences. From this standpoint, in drug discovery and design, the ability to make working hypothesis on how a small molecule interacts with its biological target can lead to rational approaches for the developing of new drug candidates.
Nowadays is possible to model the behaviour of chemical systems up to the atomistic scale, allowing retrieve insights on mechanisms behinds the ligand binding and unbinding from a receptor. Among the computational techniques available, molecular dynamics is able to take in account fundamental aspects linked to the time evolution of a biological system, such as structural flexibility and the dynamic role of water molecules in the protein binding sites.
During this Ph.D. project we employed molecular dynamics in order to disclose putative binding mechanisms of several ligands: more precisely, we applied the supervised molecular dynamics (SuMD) technique to decipher the binding pathways of both allosteric modulators and agonists to the adenosine receptors subtypes (belonging to class A of G protein-coupled receptors). Interestingly, findings highlights the coexistence of different potential recognition pathways that anticipate the formation of the orthosteric intermolecular complexes, as well as the crucial role of residues located at the extracellular portion of the protein.<br>Nel corso degli ultimi decenni, l'evoluzione tecnologica è stata così rapida da aprire la strada a una vasta gamma di approcci teorici in grado di supportare e stimolare la componente sperimentale delle scienze biologiche. Da questo punto di vista, in drug design, la capacità di fornire ipotesi di lavoro su come una piccola molecola interagisce con il suo bersaglio biologico può portare ad approcci razionali per lo sviluppo di nuovi candidati farmaci.
Oggigiorno è possibile modellare il comportamento di sistemi chimici fino alla scala atomica, consentendo di avere informazioni sul meccanismo che guida associazione e dissociazione da un recettore. Tra le tecniche di calcolo disponibili, la dinamica molecolare è in grado di prendere in considerazione fondamentali aspetti legati all'evoluzione temporale di un sistema biologico, quali la flessibilità strutturale e il ruolo dinamico delle molecole d'acqua nei siti di legame proteici.
Durante questo progetto di dottorato di ricerca abbiamo impiegato la dinamica molecolare al fine di rivelare i possibili meccanismi di riconoscimento di diversi ligandi, soprattutto nei confronti dei sottotipi recettoriali dell'adenosina (appartenenti alla classe A dei recettori accoppiati a proteine G): più precisamente, abbiamo applicato tecniche di dinamica molecolare supervisionata (SuMD) sia a modulatori allosterici che ad agonisti. E' interessante notare che i risultati evidenziano la co-esistenza di diversi possibili meccanismi di riconoscimento, che anticipano la formazione dei complessi intermolecolari ortosterici, oltre ad il ruolo cruciale di residui localizzati nella porzione proteica extracellulare.
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Wong, Kar-ho. "Luminescent cyclometalated platinum(II) and gold(III) complexes for molecular recognition and DNA binding studies /." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B20357874.
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Ferrario, Maria Giovanna. "On the recognition of ecdysteroids by the ecdysone receptor : a computational study." Strasbourg, 2010. https://publication-theses.unistra.fr/restreint/theses_doctorat/2010/FERRARIO_Maria_Giovanna_2010.pdf.
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Salim, Mahboob. "Understanding the molecular basis of γδ T cell receptor ligand recognition in cellular stress surveillance". Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4537/.
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γδ T-cells are unconventional lymphocytes hypothesised to act at the interface between innate and adaptive immunity. Emerging evidence indicates γδ T-cells play important, nonredundant roles in lymphoid stress surveillance during infection and tumourigenesis, and γδ T-cell-focussed immunotherapy trials suggest their potential exploitation in cancer immunotherapy. However, the molecular basis of γδ TCR/ligand recognition is poorly understood. In this thesis I first focussed on ligand recognition by the LES TCR, which is derived from a Vδ2-negative T-cell and mediates TCR-dependent recognition of CMVinfected cells and tumour cell lines by binding to Endothelial Protein C Receptor (EPCR). After producing LES TCR in a conformationally correct form, I used mutagenesis to map the LES TCR binding site on EPCR. Importantly, EPCR was recognised independently of bound lipid, suggesting it acts as a stress ligand rather than an antigen presenting molecule, and highlighting the importance of TCR-extrinsic factors in recognition. Secondly, I determined an NMR structure of Skint-1, a selecting ligand for mouse skin-resident DETC γδ T-cells that play important roles in immunoregulation and tumour immunosurveillance. This emphasised structural features unique to Skint-1, and suggested interaction with a separate ligand, such as the DETC TCR. Collectively, these studies improve understanding of γδ T-cell recognition.
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Schulte, Thorben Rüdiger. "Metal- and Ligand-Centered Chirality in Square-Planar Coordination Compounds." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2018. http://hdl.handle.net/21.11130/00-1735-0000-0005-126A-0.
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黃家豪 and Kar-ho Wong. "Luminescent cyclometalated platinum(II) and gold(III) complexes for molecular recognition and DNA binding studies." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31221919.
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Grassein, Paul. "Simulation of receptor-ligand recognition mechanisms of human Glutahione Transferases by free energy landscape calculation : Applications to the science of taste and cancer." Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCK013.
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Les protéines hGSTs (Glutathions Transférases humaines) sont des enzymes qui jouent un rôle majeur dans la détoxification de notre organisme et qui sont impliquées dans le développement du cancer. Le mécanisme moléculaire par lesquel les hGSTs sélectionnent une grande diversité de ligands (médicaments, pesticides...) est incompris jusqu’à ce jour. Comprendre les mécanismes de reconnaissance ligand‐récepteur des hGSTs est un enjeu fondamental majeur aux implications sociétales et économiques fortes pour la recherche sur le cancer et pour les industries agroalimentaire et pharmaceutique (cf. projet détaillé). Dans cette thèse nous utiliserons des moyens de calcul à haute performance pour réaliser des simulations de dynamique moléculaire tout atome en solvant explicite des hGSTs (système de plusieurs centaines de milliers d’atomes). L’équipe a une grande expérience de ce type de défis numériques acquise avec la simulation des protéines chaperones HSP. L’approche novatrice de l’analyse des paysages d’énergie libre des HSP développé récemment dans l’équipe sera adaptée à l’étude des GSTs et une nouvelle modélisation du paysage d’énergie libre (couplage de l’approche de Landau et de la dynamique moléculaire) sera développée dans la thèse pour élucider les mécanismes ligand‐récepteur des GSTs. Des ligands odorants et issus de la chimiothérapie seront utilisés comme modèles et les résultats théoriques seront comparés aux données expérimentales obtenues par différentes techniques (calorimétrie, fluorescence, interférométrie de bio‐couches , nanosondes) à l’Université de Bourgogne<br>The hGSTs (Human Glutathione Transferases) proteins are enzymes which play a major role in the detoxification of our organism and which are involved in the development of cancer. The molecular mechanism by which the hGSTs select a wide variety of ligands (drugs, pesticides, etc.) is not understood to this day. Understanding the mechanisms of ligand-receptor recognition of hGSTs is an issue with a major societal and economic implication for the research on cancer and for the agro-food and pharmaceutical industries (see detailed project). In this thesis we will use high performance computing means to carry out simulations of molecular dynamics any atom in explicit hGSTs solver (system of several hundred thousand atoms). The team has extensive experience with this type of digital challenge acquired with the simulation of the HSP chaperone proteins. The approach of the free energy landscape analysis of developed HSPs recently in the team will be adapted to the study of GSTs and a new modeling of the free energy landscape (coupling of the Landau approach and of the molecular dynamics) will be developed in the thesis to elucidate the ligand-receptor mechanisms of GSTs. Odorous ligands derived from chemotherapy will be used as models and the theoretical results will be compared to experimental data obtained by different techniques (calorimetry, fluorescence, bio-layer interferometry, nanosondes) at the University of Burgundy
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Ferruz, Capapey Noelia 1988. "Understanding ligand-receptor recognition by means of high-throughput molecular dynamics : a perspective for drug discovery." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/363212.
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Understanding how receptor-ligand interactions occur is a first step towards designing new drugs. The complete reconstruction of the binding process in a drug-receptor system provides all the physical-chemistry variables for rational design of inhibitors of a chosen target, an important step in drug discovery. Although very powerful, direct experimental observation of full binding processes is very hard to perform.
In this thesis, by using high-throughput molecular dynamics in the distributed computing project GPUGRID.net and analysing the resulting data by Markov state models (MSM), we successfully estimated kinetics, thermodynamics and binding modes for different molecular systems. In the initial works, we focused on estimating the potency of inhibitor-protein complexes. In subsequent studies, we described more complex pictures of binding, taking into account the receptor dynamics or other binding molecules. The results are promising and establish the methodology as a very powerful tool in the first stages of the drug discovery pipeline.<br>Comprender las interacciones entre proteína y ligando es el
primer paso para diseñar nuevos medicamentos. Llegar a reconstruir
completamente este proceso de unión proporciona todas las
variables físico-químicas para una optimización racional, un paso
muy importante en el descubrimiento de fármacos. Pese a que esto
ofrece muchas ventajas, todavía es complicado observar estos
procesos experimentalmente. En esta tesis, utilizando simulaciones
moleculares de alto rendimiento (HTMD) mediante el proyecto
distribuido GPUGRID.net y análisis por Markov state models
(MSM), hemos obtenido datos cinéticos, termodinámicos y modos
de unión para varios sistemas. En los primeros trabajos nos
centramos en estimar la afinidad entre complejos inhibidor-proteína.
En trabajos posteriores, logramos caracterizar completamente rutas
de unión del ligando teniendo en cuenta los confórmeros de la
proteína u otros ligandos presentes. Los resultados son
prometedores y establecen la utilidad de HTMD en las primeras
fases de descubrimiento de fármacos
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Sjöström, Anna. "Dynamics of MHC class 1 recognition by natural killer cells - from receptor modulation to ligand acquisition /." Stockholm : [Karolinska institutets bibliotek], 2002. http://diss.kib.ki.se/2002/91-7349-204-3.
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Racys, Daugirdas. "Synthesis of multifunctional ensembles for asymmetric catalysis and chiral recognition : investigation of palladium-trost ligand complexes." Thesis, University of Bristol, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.680110.
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The palladium complex 1, bearing the Trost 'Standard' Ligandi (TSL) 2 is an efficient and highly selective catalyst used to facilitate asymmetric allylic alkylation. Earlier research conducted by Lloyd Jones and co-workers suggested that the selectivity of the catalyst 1 monomeric species may arise via ligand-accelerated catalysis pathway. TSL 2 has a degree of flexibility that is crucial for the selectivity, but also responsible for the rapid equilibrium of the Pd-TSL monomers 1 with the low selectivity and diminished activity oligomers (I)n. The oligomers (I)n are known to be the dominant catalyst 1 species at higher concentrations responsible for effects observed and are memory in allylic alkylation catalytic cycle. The aim of this work was to further develop the understanding of the aggregated catalyst (I)n. n 1 {(1 )4}n Small-angle neutron scattering (SANS) revealed that Pd-TSL oligomers (I-BArF)n readily aggregate to form cylinders in common organic solvents. According to molecular mechanics modelling at MM3 theory level the architecture is the most consistent with linear stacks of cyclic disc-shaped tetramers {(I-BArF)4}n. In low polarity solvents the rods can grow up to ~200 A long and may contain between 10 to 14 tetramer discs (1)4, sandwiched with bulky BArF anion layers. In polar organic media the solvation is more effective and shorter (30 A) stacks were detected by SANS. Molecular dynamics simulations also supported these observations. Finally, the kinetic SANS experiments showed that the architecture remains effectively unchanged during the catalytic cycle. 1< ~ 200A >1 16-20 A 31p NMR measurements, however, indicated that the highest concentration of monomer 1 with only trace amounts of oligomer {(I)4}n is accessible in very dilute dichloromethane solution of < 4 mM. In contrast, high dielectric constant solvents favour almost complete oligomerisation. Further experiments focused on the structure of {(I-BArF)4}n racemic mixtures. SANS measurements required the complementary perdeuterated complex [Dd-I-BArF. An enantiopure, deuterium labelled [Dd-I-BArF pseudo-enantiomer was prepared by a new divergent synthetic route of 8 steps in the longest linear branch and employing simple commercially available starting materials. SANS data analysis indicated that [Dd-I-BArF formed shorter cylinders than I-BArF. However, the measurements were not sensitive enough to resolve the exact composition of pseudo-racemic mixtures [DoID47I-I-BArF.
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Simões, Inês Tadeu dos Anjos. "Functional and therapeutical implications of ligand recognition by the scavenger-like lymphocyte receptors CD5 and CD6." Master's thesis, Faculdade de Ciências e Tecnologia, 2011. http://hdl.handle.net/10362/6582.
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Dissertação para obtenção do Grau de Mestre em
Genética Molecular e Biomedicina<br>The CD5 and CD6 lymphocyte surface receptors are highly homologous members of the
Scavenger Receptor Cystein Rich (SRCR) superfamily mainly expressed by all T lymphocytes and the B1a subpopulation of B cells. Although the ultimate function/s are far from being completely understood, CD5 and CD6 are known to play a relevant role in both lymphocyte development and
differentiation by negatively modulating the survival/death-inducing intracellular signals generated during the antigen recognition. Recently, this group has developed a transgenic mouse line which
expresses a soluble form of human CD5, likely blocking the ligand-receptor interactions mediated by CD5 and interfering with normal lymphocyte response.
This study was aimed at furthering the study of the recombinant soluble human CD5 Transgenic(rshCD5Tg) mouse phenotypical analysis, its response to antigen stimuli and tumor implantation; the function of rshCD6 was also tested.
It was observed that rshCD5Tg mice display an exacerbated immune response, likely due to a reduction in the number of T and B cells with regulatory/suppressive function (Treg, B1a, B10 cells) and the increase in effector cells (NKT, MZ B cells). In agreement with these phenotypical
characteristics, the functional analysis of rshCD5Tg mice showed enhanced immune responses to Tdependent and –independent antigens, as well as enhanced anti-tumoral responses, with or without concomitant chemotherapy treatment. Importantly, both the phenotypical and functional findings
could be reproduced in wild-type mice following prolonged infusion of purified exogenous rshCD5 protein.
Overall, these results argue in favor of a relevant role of CD5-mediated molecular interactions in the homeostasis of functionally relevant lymphocyte subpopulations and open the possibility for CD5-based therapeutical interventions in different disease settings such as cancer, infection and immunodeficiency.
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Davis, Caroline M. "Investigation and Characterisation of Protein-Ligand Interactions: SRA-Ribonucleic Acid Recognition and Anti-Microbial Drug Discovery." University of Akron / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=akron1437779075.
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McAtamney, Sarah. "Investigation of Dengue Fever Virus Envelope Glycoprotein Carbohydrate-Ligand Recognition Events Essential for Mammalian Cell Infection." Thesis, Griffith University, 2009. http://hdl.handle.net/10072/366363.
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Dengue Fever virus (DENV) is a very old mosquito-borne flavivirus that has made a modern worldwide re-emergence as a result of population movement and growth, urbanisation and lapse of vector control. The World Health Organisation estimates that 2.5 billion people, or two-fifths of the world’s population are at risk from DENV, which can cause serious illness and in its severe forms, death. Despite the humanitarian and economic burden that DENV and its flaviviral relatives create, there are no chemotherapeutic drugs available and vaccine development is challenging. Mammalian host cell infection by DENV is mediated by the Envelope glycoprotein (EGP), which covers the entire exposed surface of the mature virus particle and is comprised of three exposed protein domains (DI, DII and DIII) and a transmembrane anchor. While significant effort has been invested to better understand how DIII of EGP participates in receptor mediated endocytosis of DENV into host cells, including the site and structure of the receptor binding site, or carbohydrate recognition domain (CRD), and the structure of ligands involved remain undefined. A recent study of mammalian cell surface glycans involved in DENV infection by Dr Kazuya Hidari and co-workers identified DENV inhibition by the glycolipid Paragloboside, which includes the tetrasaccharide Lacto-N-neotetraose (nLc4)1. This thesis reports an investigation of DENV-2 EGP DIII ligand specificity and characterisation of the DIII CRD involved in mammalian cell infection. To achieve this, soluble and high level expression of DENV-2 ThNH-7/93 EGP DIII was established from Pichia pastoris (P. pastoris) yeast and the recombinant DIII was successfully purified to near homogeneity by single step affinity chromatography. The biological activity of DIII was assessed by DENV permissible cell based assays and the recombinant protein was shown to have retained its wildtype host cell receptor binding activity. Recombinant DIII protein was utilised to successfully establish glycan microarray and saturation transfer difference nuclear magnetic resonance (STD NMR) methodologies, Confidential – not to be copied ii which are useful in the study of EGP ligand specificity. Investigation of nLc4 ligand binding to EGP confirmed that this tetrasaccharide binds to the CRD DIII, involving each of its carbohydrate moieties. Epitope mapping by STD NMR spectroscopy also revealed that the H-1 proton of the N-acetyl-D-glucosamine (GlcNAc) makes closest contact with DIII via its N-acetyl group. Screening of carbohydrate libraries with DENV-2 and a multivalent DIII complex identified additional EGP specificity to several novel binding ligands that share a GlcNAc moiety at the first or second non-reducing cytoplasmexposed positions.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>Institute for Glycomics<br>Full Text
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Hanske, Jonas [Verfasser]. "Investigation of the Structural Basis of Ligand Recognition of the C-Type Lectin Receptor Langerin / Jonas Hanske." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1121587895/34.
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Dyachenko, Andrey. "Molecular recognition in gas phase: theoretical and experimental study of non-covalent protein-ligand complexes by mass-spectrometry." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/113301.
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In the present thesis we have explored different factors that impede accurate quantitative description of non-covalent protein-protein and protein-ligand interactions and design of new potent and specific binders from the scratch. Firstly, we addressed the role of solvent in the mechanism of non-covalent interactions. Secondly, we tackled the question about the intrinsic conformational flexibility of the protein molecules and the part it plays in weak interactions between proteins.
In the first part of the thesis we studied the interactions of vascular endothelial growth factor (VEGF) protein with five cyclic peptides in solution and gas phase. The results showed that affinities of five ligands to VEGF in solution and gas phase are ranked in inversed order. That is, the that has the highest affinity in solution (as shown by chemical shift perturbation NMR and isothermal titration calorimetry) forms the weakest complex with VEGF in gas phase, and vice versa. We compared gas-phase and solution binding affinities of of five peptides and made qualitative conclusions about the role of the solvent in protein-ligand interactions.
In order to obtain more quantitative information about the gas-phase behavior of non-covalent complexes we have developed a combined experimental/theoretical approach to study the energetics of collisional activation of the ion prior to dissociation. We applied developed strategy to model CID in traveling wave ion guide (TWIG) collision cell. We validated the model on the CID of leu-enkephalin peptide and then applied developed strategy to five non-covalent protein-peptide complexes and found activation energies of their dissociation reactions.
Next we applied ESI native MS to study the allosteric interactions between the molecular chaperonin GroEL and ATP. The obtained data allowed to construct a scheme of conformational transition of GroEL upon binding of ATP and distinguish between two different cooperativity models, providing strong arguments in favor of Monod-Wyman-Changeux (MWC) model.
Finally, be studied the backbone dynamics of VEGF with a combination of NMR relaxation and all-atom force-field based normal mode analysis (NMA). We showed that combination of experimental and computational approach allows to identify flexible zones with higher level of confidence. We also found out that residues, that are involved VEGF-receptor interactions, reside in or close to the flexible zones, suggesting the critical role conformational plasticity plays in the non-covalent protein-protein interactions.<br>Las biomoléculas de los organismos vivos realizan sus funciones principalmente a través de interacciones débiles reversibles entre ellas. La transducción de señal, la replicación de ADN/ARN, otros procesos enzimáticos y, virtualmente, cualquier otro proceso involucrado en las funciones vitales de cualquier organismo vivo (de las simples amebas, al complejo ser humano), requiere que las moléculas “hablen” entre ellas. Dicho lenguaje se basa en interacciones no covalentes.
La flexibilidad conformacional es una propiedad esencial de las grandes biomoléculas, y muchas de las funciones desempeñadas por proteínas se basan en su capacidad para cambiar de conformación en respuesta a un factor externo. Geométricamente hablando, la presencia de flexibilidad en una proteína obstaculiza el diseño racional de medicamentos porque posibilita la existencia de un número muy elevado de conformaciones de dicha proteína. Por este motivo, cualquier información sobre la flexibilidad de una proteína es sumamente valiosa para la comprensión de PPI y PLI y para el diseño racional de medicamentos. Los capítulos 1-3 de la presente tesis versan sobre la solvatación, mientras que la flexibilidad se estudiara en el capitulo 4.
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Schafer, Jamie Lynn. "Rhesus macaque KIR recognition of MHC class I molecules: Ligand identification and modulation of interaction by SIV peptides." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11683.
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Natural killer (NK) cells can kill virus-infected cells without prior antigenic exposure, and are therefore important for controlling viral replication prior to the onset of adaptive immune responses. Primate NK cells express activating and inhibitory killer-cell immunoglobulin-like receptors (KIRs) that bind to specific major histocompatibility complex (MHC) class I molecules. The importance of KIR interactions with MHC class I in human immunodeficiency virus (HIV) pathogenesis is demonstrated by the association of select KIR and MHC class I genotypes with delayed progression to acquired immunodeficiency syndrome (AIDS).
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Herbert, Paul. "The heteromeric 5-HT3A/B receptor : the effect of 5-HT3B subunits on receptor structure and ligand recognition." Thesis, Aston University, 2008. http://publications.aston.ac.uk/11070/.
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The 5-HT3 receptors are members of the cys-loop family of ligand-gated ion channels. Two functional subtypes are known, the homomeric 5HT3A and the heteromeric 5HT3A/B receptors, which exhibit distinct biophysical characteristics but are difficult to differentiate pharmacologically. Atomic force microscopy has been used to determine the stoichiometry and architecture of the heteromeric 5HT3A/B receptor. Each subunit was engineered to express a unique C-terminal epitope tag, together with six sequential histidine residues to facilitate nickel affinity purification. The 5-HT3 receptors, ectopically expressed in HEK293 cells, were solubilised, purified and decorated with antibodies to the subunit specific epitope tags. Imaging of individual receptors by atomic force microscopy revealed a pentameric arrangement of subunits in the order BBABA, reading anti-clockwise when viewed from the extracellular face. Homology models for the heteromeric receptor were then constructed using both the electron microscopic structure of the nicotinic acetylcholine receptor, from Torpedo marmorata, and the X-ray crystallographic structure of the soluble acetylcholine binding protein, from Lymnaea stagnalis, as templates. These homology models were used, together with equivalent models constructed for the homomeric receptor, to interpret mutagenesis experiments designed to explore the minimal recognition differences of both the natural agonist, 5-HT, and the competitive antagonist, granisetron, for the two human receptor subtypes. The results of this work revealed that the 5-HT3B subunit residues within the ligand binding site, for both the agonist and antagonist, are accommodating to conservative mutations. They are consistent with the view that the 5-HT3A subunit provides the principal and the 5-HT38 subunit the complementary recognition interactions at the binding interface.
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Sharma, Sumana. "Genome-scale identification of cellular pathways required for cell surface recognition." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/271825.
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A range of biochemically diverse molecules located in the plasma membrane— such as proteins, glycans, and lipids—mediate cellular recognition events, initiation of signalling pathways, and the regulation of processes important for the normal development and function of multicellular organisms. Interactions mediated by cell surface receptors can be challenging to detect in biochemical assays, because they are often highly transient, and membrane-embedded receptors are difficult to solubilise in their native conformation. The biochemical features of low-affinity extracellular protein interactions have therefore necessitated the development of bespoke methods to detect them. Here, I develop a genome-scale cell-based genetic screening approach using CRISPR-Cas9 knockout technology that reveals cellular pathways required for specific cell surface recognition events. Using a panel of high-affinity monoclonal antibodies, I first establish a method from which I identify not only the direct receptor but also other required gene products, such as co-receptors, post-translational modi cations, and transcription factors contributing to antigen expression and subsequent antibody-antigen recognition on the surface of cells. I next adapt this method to identify cellular factors required for receptor interactions for a panel of recombinant proteins corresponding to the ectodomains of cell surface proteins to the endogenous surface receptors present on a range of cell lines. In addition to finding general cellular features recognised by many ectodomains, I also identify direct interaction partners of recombinant protein probes on cell surfaces together with intracellular genes required for such associations. Using this method, I identify IGF2R as a binding partner for the R2 subunit of GABAB receptors, providing a mechanism for the internalisation and regulation of GABAB receptor signalling. The results here demonstrate that this single approach can identify the molecular nature and cell biology of surface receptors without the need to make any prior assumptions regarding their biochemical properties.
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Schopis, Jia L. "Drug Discovery Studies of the T box Riboswitch: Potential Ligand Inhibition andCofactor Modulation of the tRNA-Antiterminator Complex Recognition." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1461674214.
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Ruiz, Botella Sheila. "The importance of ligand design for the development of supramolecular catalysts and ion receptors." Doctoral thesis, Universitat Jaume I, 2017. http://hdl.handle.net/10803/402550.
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La tesis está dividida en dos partes claramente diferenciadas. La primera parte trata sobre aspectos concernientes a la catálisis supramolecular. Los trabajos descritos están basados en el diseño de nuevos ligandos N-heterociclicos con diferentes topologías y funcionalidades, los cuales fueron coordinados a diferentes centros metálicos. Los complejos sintetizados fueron caracterizados y estudiados en catálisis, con el objetivo principal de estudiar los efectos producidos por los ligandos orgánicos debido a interacciones del tipo no covalentes. Estos complejos o catalizadores también fueron soportados y estudiados en catálisis heterogénea.
La segunda parte de la tesis se centra en estudios de química supramolecular host-guest. Los trabajos descritos en esta parte describen la preparación de nuevos receptores ionicos basados en esqueletos de resorcinareno cavitando y/o esqueletos de naturaleza tripodal. Se estudiaron y analizadores los diferentes modos de interacción y las constantes de asociación hacia una gran variedad de guests de diferente naturaleza.<br>The present thesis is divided in two different parts. Part 1 is titled the importance of ligand design for the development of supramolecular catalysts. This part includes three different chapters: introduction chapter 1, chapter 2 and chapter 3. Chapter 1 shows a brief overview of the most interesting items related to supramolecular catalysis. In chapter 2 is described the synthesis and characterization of three different p-xylylbis-benzimidazolylidene iridium and rhodium complexes. Chapter 3 reports the synthesis, characterization and catalytic studies of different palladium, iridium and rhodium complexes, which are formed by N-heterocyclic ligands featuring different topologies, and some of them decorated with pyrene functionalities. The importance and influence of these ligands in the conformational and catalytic behaviour of the metal complexes is studied in detail, providing evidences of the effects produces due to non-covalent interactions such as π-π interactions.
Part 2 is titled the importance of ligand design for the development of ion receptors. This part includes three chapters: introduction chapter 4, chapter 5 and chapter 6. Chapter 4 is a brief introduction of the most relevant aspects related to supramolecular host-guest chemistry. The approaches described in chapter 5 consist of two different strategies for the preparation of imidazole resorcinarene based cavitands for the recognition of anions or cations. Chapter 6 reports the synthesis of tris-azolium and tris-iodoazolium tripodal receptors for the recognition of anions. In both chapters (5 and 6) are studied the binding capabilities of the receptors towards several ions, showing the importance of the development in ligand design to improve the properties of the receptors.
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Pathak, Asmita. "Protection Against Atherosclerosis by A Non-native Pentameric CRP that Shares its Ligand Recognition Functions with an Evolutionarily Distant CRP." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etd/3759.
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C-reactive protein (CRP) is an acute phase protein of the innate immune system that has been evolutionarily conserved. Human CRP is known to exist in two different pentameric conformations; native CRP and non-native CRP that possess differential ligand recognition functions. The structure of CRP evolved from arthropods to humans, in terms of subunit composition, disulfide bonds, and glycosylation pattern. Along with change in structure, the gene expression pattern of CRP also evolved from a constitutive protein in lower invertebrates to an acute phase protein in humans. The objective of this study was to determine the function of a non-native pentameric CRP, that binds to atherogenic LDL, in atherosclerosis and compare the ligand recognition functions of human pentameric CRP with an evolutionary distant CRP for understanding the evolution of the structure of CRP. Additionally, in vitro reporter gene assays were used to gain further insight into the regulation of human CRP gene expression by an IL-6 inducible transcription factor, STAT3. We observed that CRP, in its non-native pentameric conformation, binds to atherogenic LDL and slows the progression of atherosclerosis in a site-specific manner in high fat diet fed LDLR-/- mice. Further, we observed that the ligand recognition function of CRP from an evolutionary conserved species, Limulus polyphemus, is different than that of native pentameric human CRP, but overlaps that of non-native pentameric human CRP. Lastly, we screened the proximal 300 bp region of the CRP promoter and identified a novel STAT3 binding site at position -134 located upstream of the previously identified, transcriptionally active STAT3 site at -108. In conclusion, non-native pentameric human CRP is an atheroprotective molecule whose ligand recognition functions exhibit similarity with CRP from an evolutionarily distant species. IL-6 mediated transcriptional regulation of human CRP is modulated, in part, by STAT3 binding to two distinct positions on the CRP promoter.
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Park, In-Hee. "Computational Simulations of Protein-Ligand Molecular Recognition via Enhanced Samplings, Free Energy Calculations and Applications to Structure-Based Drug Design." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1276745410.
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Nutiu, Razvan Li Yingfu. "Fluorescent functional DNA for bioanalysis, drug discovery and nanotechnology." *McMaster only, 2006.
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Wiesner, Silke. "NMR studies of the yeast splicing factor Prp40 structures and ligand recognition of a WW domain pair and an FF domain /." [S.l. : s.n.], 2003. http://www.diss.fu-berlin.de/2003/66/index.html.
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Frieg, Benedikt [Verfasser], and Birgit [Gutachter] Strodel. "Integrative modeling of function-associated molecular recognition in protein-ligand, protein-peptide, and protein-protein complexes / Benedikt Frieg ; Gutachter: Birgit Strodel." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1203872445/34.
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Patschull, Lafitte-Laplace Anathe Olivia Maria. "In silico ligand fitting/docking, computational analysis and biochemical/biophysical validation for protein-RNA recognition and for rational drug design in diseases." Thesis, Birkbeck (University of London), 2014. http://bbktheses.da.ulcc.ac.uk/84/.
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Kaposi’s sarcoma-associated herpesvirus, is a double-stranded DNA γ - herpesvirus and the main causative agent of Kaposi’s sarcoma (KS). γ - herpesviruses undergo both lytic and latent replication cycles; and encode proteins that modulate host transcription at the RNA level, by inducing decay of certain mRNAs. Here we describe a mechanism that allows the viral endo-/exonuclease SOX to recognise mRNA targets on the basis of an RNA motif and fold. To induce rapid RNA degradation by subverting the main host mRNA degradation pathway SOX was shown to directly bind Xrn1. This may shed light as to how some viruses evade the host antiviral response and how mRNA degradation processes in the eukaryotic cell are involves in this.
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Carmo, dos Santos Nadia A. "Syntheses and application of nitrogen based polydentate ligand complexes." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3427281.
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This Ph.D. thesis describes the versatility of metal complexes with tris(2-pyridylmethyl)amine (TPMA) based ligands to be used either as self-assembling molecular scaffolds with application on molecular recognition and chiroptical probing, or as active catalysts in atom transfer radical polymerization and hydrogen evolving catalysis reactions. Quantitative chirality determination is fundamental due to the broad effect that stereochemistry has in many different scientific fields. Within this subject, there is a strong urge to develop fast and effective methods to perform stereochemical analysis to couple with high throughput screening methods for production or analysis of biological samples. Chiroptical methods are able to provide the speed and accuracy that enantiomeric excess determination measurement needs. Within that scope, three molecular probes for amino acids have been developed allowing to perform enantiomeric determination and absolute configuration by measuring the induced circular dichroism (CD), vibrational circular dichroism (VDC) or circularly polarized luminescence (CPL). The reported systems were able to provide reliable information about the chirality of the studied analytes.
In this dissertation the mechanistic investigation for the elucidation of the self-assembly process of TPMA with amino acids and metals is described. The complex equilibrium that yields the dimeric supramolecular architectures responsible for the chiroptical signals is exposed. The main factor that affects the final products of the reaction as well. Then the effects on the chiroptical response when changing the metal ions on the main structure are reported. Some impressive results were obtained by using Co (II) instead of Zn (II) on the VCD measurements. It was actually possible to enhance the signal intensity by two orders of magnitude. Furthermore, after modifying the initial ligand structure to add a quinolinic moiety in order to give fluorescent properties to the system, it was possible to obtain CPL bands.
Moreover, the versatility of the studied ligands was assessed in other areas like catalysis. Eight novel copper complexes were synthesized and applied as active catalysts in atom transfer radical polymerization (ATRP). Hidroxyquinolinic based cobalt, nickel and iron complexes were evaluated as potential catalysts for hydrogen evolving reactions with positive results.<br>Questa tesi di dottorato descrive la versatilità dei complessi metallici con leganti tris(2-piridilmetil)amminici (TPMA) da utilizzare come scaffold molecolari autoassemblanti con applicazione sul riconoscimento molecolare e sonde chiroptiche, o come catalizzatori attivi nella polimerizzazione radicale a trasferimento atomico e reazioni di catalisi di sviluppo di idrogeno. La determinazione quantitativa della chiralità è fondamentale a causa dell'ampio effetto che la stereochimica ha in molti campi scientifici diversi. All'interno di quest’area, esiste una grande necessità di sviluppare metodi rapidi ed efficaci per eseguire analisi stereochimiche da abbinare a metodi di screening ad alto rendimento per la produzione o l'analisi di campioni biologici. I metodi chiropici sono in grado di fornire la velocità e la precisione necessarie per la determinazione dell’eccesso enantiomerico. Con questo obiettivo sono state sviluppate tre sonde molecolari per amminoacidi che consentono di eseguire la determinazione enantiomerica e la configurazione assoluta misurando il dicroismo circolare indotto (CD), il dicroismo circolare vibrazionale (VDC) o la luminescenza circolare polarizzata (CPL). I sistemi riportati sono stati in grado di fornire informazioni affidabili sulla chiralità degli analiti studiati.
In questa dissertazione viene descritta l'indagine meccanicistica per la delucidazione del processo di auto-assemblaggio di TPMA con amminoacidi e metalli. Viene esposto il complesso equilibrio che produce le architetture supramolecolari dimeriche responsabili dei segnali chiropici. Il fattore principale che influisce anche sui prodotti finali della reazione. Quindi vengono riportati gli effetti sulla risposta chiropica al cambiare degli ioni metallici sulla struttura principale. Alcuni risultati significativi sono stati ottenuti utilizzando Co (II) invece di Zn (II) sulle misurazioni VCD. In realtà è stato possibile aumentare l'intensità del segnale di due ordini di grandezza. Inoltre, dopo aver modificare la struttura del legante iniziale per aggiungere un gruppo chinolinico al fine di conferire proprietà fluorescenti al sistema, è stato possibile ottenere le bande CPL.
In aggiunta, la versatilità dei leganti studiati è stata valutata in altre aree come la catalisi. Otto nuovi complessi di rame sono stati sintetizzati e applicati come catalizzatori attivi nella polimerizzazione radicale a trasferimento atomico (ATRP). I complessi cobalto, nichel e ferro idrossichinolinici sono stati valutati come potenziali catalizzatori per reazioni di sviluppo di idrogeno con risultati positivi.
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Romuald, Camille. "Des Muscles Moléculaires dans tous leurs Etats aux Noeuds Moléculaires inédits à Cavité Modulable." Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20167.
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Cette thèse est dédiée à la conception de machines moléculaires pH-sensibles inédites de type muscles et nœuds moléculaires. Le premier muscle moléculaire pH-sensible a été synthétisé de manière très directe, et publié en 2008, en utilisant une stratégie en deux étapes: 1) fermeture des axes encapsulés par cycloaddition 1,3-dipolaire de type Huisgen catalysée par le cuivre (I), 2) méthylation des triazoles formés en triazoliums, capables d'être reconnus par les macrocycles DB24C8. Deux états étirés ou contractés, déclenchés par simple variation de pH, permettent le contrôle de l'orientation et de la distance entre les deux « stoppeurs » glucidiques non reliés de manière covalente. Des stations pyridiniums amides mono ou disubstitués inédites ont également été utilisées pour la synthèse de muscles moléculaires de plus large amplitude à effets co-conformationnels induits. Lors de la contraction du muscle par carbamoylation des ammoniums, la différence de localisation des macrocycles autour des stations pyridiniums amides, dépendante de la substitution des amides, engendre deux effets très différents : rôle de frein moléculaire de la DB24C8 ou basculement conformationnel impressionnant des chaises des mannopyranoses. Une étude méthodologique a été menée afin de classer les stations moléculaires rencontrées dans ce manuscrit, selon leurs affinités respectives pour la DB24C8, et a conduit à la conception d'un muscle moléculaire oscillant dont l'état varie continuellement entre contracté et semi-contracté en fonction de la température et de la nature du solvant. Enfin, différentes stratégies de synthèse ont été explorées pour obtenir des nœuds moléculaires inédits en forme de double lasso par cyclisation de synthons dimères de rotaxanes. Un double lasso dont la vitesse de rotation et la taille de la cavité peuvent être modulées en fonction du pH a ainsi été obtenu<br>This thesis is devoted to the synthesis of pH-sensitive molecular muscles and knots. The first molecular muscle has been readily synthesized and published in 2008, using a two-step strategy: 1) end-capping of the interlocked axles by copper(I)-catalyzed Huisgen alkyne-azide 1,3-dipolar cycloaddition, 2) methylation of triazoles to triazoliums, which are able to interact with the macrocycle DB24C8. Two stretched and contracted states, triggered by variation of pH, allow the control of the distance and of the orientation of the two glucidic ends, which are not covalently linked. Novel mono- and disubstituted pyridinium amide stations have been used for the synthesis of large-amplitude molecular muscles, whose translation of the macrocycles trigger a second co-conformational induced effect. In fact, upon contraction of the molecular muscle, using carbamoylation of the ammoniums, the slight different localizations of the macrocycles around the pyridinium amides (depending on their mono- or disubstitution) trigger two very different effects. The first one is a molecular break played by the DB24C8, whereas the second one is a flipping of the chair-like conformation of the mannopyranosyl ends. A methodologic study was then carried out with the aim to determine the relative affinity of the new described molecular stations for the DB24C8, and led to the synthesis of a molecular muscle which oscillates from the contracted to the semi-contracted co-conformation, depending on solvent and temperature. Eventually, different routes to very new double-lasso molecular knots were investigated from a molecular muscle building-block. One molecular knotted machine has been obtained, and has a double-lasso structure, whose rotation and size of its cavity can both been modulated by variation of pH
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Negroni, Maria P. "Studies in Antigen Presentation and Antigen Recognition at Different Interfaces of the Adaptive Immune System." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/996.
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Antigen presentation and recognition are key processes of the immune system necessary to initiate the adaptive immune response. Longstanding goals of these fields have been to understand the molecular mechanism of MHC II-peptide binding, the way in which dysregulation of this process can lead to disease, and determining how γδTCRs recognize their ligands. To examine some of these outstanding questions, I designed photocleavable peptides that could bind HLA-DR1 and could be used to facilitate peptide exchange. I also performed studies to understand whether peptide exchange on HLA-DR1 can be affected by glycation modifications, which occur in hyperglycemic conditions such as diabetes. I observed that while glycation modifications on HLA-DR1 did not affect peptide exchange, these modifications decreased the catalytic effect of HLA-DM on this reaction, which could affect antigen presentation in diabetic patients. For studies on antigen recognition by γδTCRs, I focused on γδNKT cells, a subset of γδT cells known to play a role during Listeria infection. I used four different variants of the γδNKT TCR to study the restrictions on Vγ junctional region usage by this TCR for ligand recognition. I found that all the TCR variants I examined could recognize cells infected with Listeria, indicating that this TCR is not restricted by γ-chain usage in order to recognize ligand. My research generated reagents that could serve in future studies of HLA-DR1 peptide binding and contributed to understanding the effect of hyperglycemic conditions on antigen presentation, as well as provided greater understanding of γδTCR restriction for ligand recognition.
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Millman, Jonathan Scott Andrews David. "Characterization of membrane-binding by FtsY, the prokaryote SRP receptor /." *McMaster only, 2002.
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