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Jones, Susan. "Protein-protein interactions." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338952.
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Cooper, Simon T. "PAX6 protein-protein interactions." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/29070.
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The gene PAX6 is located on chromosome 11 (11p13) and encodes a transcription factor (PAX6) that is expressed early in development. The PAX6 protein is expressed in the developing eye, regions of the brain, central nervous system (CNS), nasal epithelium and pancreas. PAX6 is best known for its role eye development with heterozygous mutations causing congenital ocular malformations. However, it must be remembered that PAX6 has multiple functions in the brain including specification of neuronal subtypes and axon guidance. There is growing understanding of the role of PAX6 as a transcription factor during development, and many of its DNA targets have recently been defined. However, almost nothing is known about the proteins with which PAX6 interacts. In the initial stage of my research I identified a conserved region consisting of the final 32 amino acids of the PST (proline, serine and threonine rich) domain of PAX6. Based on sequence homology and secondary structure predictions I classed this region as a novel domain, the ‘C terminal domain’. Next I used the yeast 2-hybrid system to investigate possible PAX6 protein interactions. By screening a mouse brain cDNA library with the C terminal domain and whole PST domain, I identified three novel and interesting interactors, HOMER3, DNCL1 and TRIM11. I re-confirmed these interactions in a pairwise manner using the yeast 2-hybrid system, and I showed that the C terminal domain was vital for the interactions between PAX6 and HOMER3 or DNCL1. Furthermore, certain C terminal mutations that are known to cause ocular malformations in patients are also sufficient to reduce or abolish these interactions. I attempted to further characterise the interactions by co-immunoprecipitation. However, this was not possible due to technical difficulties.
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Xia, Zebin. "Peptidomimetics to mimic protein-protein interactions." Diss., Texas A&M University, 2003. http://hdl.handle.net/1969.1/2239.
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Quenched Molecular Dynamics (QMD) used to explore molecular conformations was developed to operate in Insight II platform for two simulation engines: CHARMm and Discover. Two scripts and procedures were written for molecular minimization, dynamics, minimization of each of several hundred conformers, and cut off. Experience with Insight II/Discover versus Quanta/CHARMm, and between Insight II/CHARMm versus Quanta/CHARMm has taught that the forcefield is the key factor in QMD studies. Protein A has been used for the purification of commercial antibodies, but it is expensive. Seven peptidomimetics of protein A were designed based on the hot-spots located at the helix-loop-helix region of protein A, and synthesized via solid phase using the Fmoc approach. These peptidomimetics were characterized by MS and NMR. The conformations of four peptidomimetics were studied by NMR and CD in water/hexafluoroisopropanol (pH 4). The CD and NMR data show that addition of hexafluoroisopropanol stabilizes their a-helical conformations. The structures of these peptidomimetics in solution were generated with Quanta/CHARMm using NMR data as limits for the QMD technique. Protein G has also been used to purify antibodies, but it is expensive too. A number of protein G mimics were designed as trivalent molecules. An efficient preparation of trivalent molecules having a useful primary amine arm has been developed through solid phase synthesis. The cheap, commercially available poly(propylene imine) dendrimers were used as scaffolds which allow multimerization of functionalized compounds. A small library of trivalent compounds were synthesized using this approach. A portion of compounds in this library were tested by Amersham Biosciences. The seven amino acid modified DAB-Am-4 exhibits strong binding to the IgG/Fab, and is a potential ligand for IgG purification. The interactions between neurotrophins (ie NGF and NT-3) and their receptors are typical drug targets. Fourteen second-generation peptidomimetics showing NGF-like or NT3-like activities in a preliminary bioassay, were resynthesized and tested again. Preliminary and retested data were compared. To access a direct binding assay, five fluorescently labeled peptidomimetics 41a-e were synthesized for a fluorescence activated cell sorting (FACScan) assay. Six monomeric precursors 42 and 43 were prepared on large scales for the library of bivalent turn analogs
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Bateman, Katherine Sophie. "Structural studies of protein, protein interactions." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0020/NQ46804.pdf.
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Laidlaw, Stephen Mark. "Protein-protein interactions of fowlpox virus." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424671.
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Bougouffa, Salim. "Empirical modelling of protein-protein interactions." Thesis, University of Manchester, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529241.
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Robinson, Ross Alexander. "Structural biology of protein - protein interactions." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504517.
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Gill, Katrina Louise. "Protein-protein interactions in membrane proteins." Thesis, University of Newcastle Upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400016.
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Richter, Carsten Detlev. "Protein-protein interactions in modular megasynthases." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612738.
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Sammond, Deanne Wallander Kuhlman Brian A. "Computational redesign of protein-protein interactions." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1822.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Dec. 11, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry and Biophysics Program in Molecular and Cellular Biophysics." Discipline: Biochemistry and Biophysics; Department/School: Medicine.
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Govers-Riemslag, Josepha Wilhelmina Philomena. "Protein-protein and protein-membrane interactions in prothrombin activation." Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1994. http://arno.unimaas.nl/show.cgi?fid=6949.
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Lendel, Christofer. "Molecular principles of protein stability and protein-protein interactions." Doctoral thesis, Stockholm, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-480.
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Kneissl, Sabine. "Photocontrol of protein-protein and protein-nucleic acid interactions." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/54835/.
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Proteins often depend on a-helices for binding to other biomacromolecules. Reversible control of a-helix stability was accomplished in previous studies by incorporating a photoisomerisable azobenzene cross-linker into peptides, subsequently enabling the optical control of DNA-protein interactions. This approach was extended in this study to include protein-protein and protein-RNA interactions. One of the primary regulatory components in apoptosis signalling is the antiapoptotic protein Bcl-xL which interacts with the a-helical BH3 domain of the Bak protein. The Rev/RRE interaction is crucially involved in the life cycle of Human Immunodeficiency Virus. These interactions were targeted by designing peptides based on the BH3 domain of Bak and on the RNA-binding domain of Rev these peptides are activated by external light pulses after the incorporation of the cross-linker. The ability to control cross-linker conformation and hence peptide secondary structure was demonstrated by CD and UV/Vis spectroscopy. The binding to the target structure and complex disruption was determined in the dark-adapted and irradiated states using fluorescence based assays. Structural studies using NMR spectroscopy demonstrated that the alkylated peptides bind to the same part of the target molecule as the wild-type peptide, regardless of their structure. Moreover, one of the BH3 domain-based peptides and the light-controllable transcription factor PhotoMyoD were modified with protein transduction domains to enable future in vivo studies. Overall, this work opens the possibility to interfere reversibly and specifically with protein-protein and protein-RNA interactions and to study and modulate cellular function by optical control.
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Chen, Dan. "Regulation of protein kinase C by protein-protein interactions /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3112821.
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Fornés, Crespo Oriol 1983. "On the characterization of protein-DNA interactions using statistical potentials and protein-protein interactions." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/320192.
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Protein-DNA interactions are indispensable players in the daily activities of cells. DNA-binding proteins regulate gene expression and are responsible of DNA replication, packaging, repair and recombination. Among them, transcription factors activate/repress gene transcription by binding to specific genomic sites. Hence, the characterization of transcription factor binding sites turns out to be crucial in order to understand gene regulation. In this context, the development of computational tools is foremost. Here, I show the prediction of redundant transcription factors in yeast using a combination of homology-based tools and protein-protein interactions. The approach was automated and incorporated into ModLink+, an online and user-friendly tool to infer the fold of remote homologs. Moreover, I describe split-statistical potentials for protein-DNA interactions. Finally, I present SHAITAN, a statistical/homology-based approach that can be used to both predict transcription factor binding sites and infer the more likely transcription factors to bind a DNA sequence of interest.Les interaccions proteïna-ADN són indispensables en l’activitat diària de les cèl•lules. Les proteïnes que participen en aquestes interaccions s’encarreguen de la regulació de l'expressió gènica i són responsables de la replicació, l'empaquetament, la reparació i la recombinació de l’ADN. Entre aquestes proteïnes, els factors de transcripció activen/reprimeixen la transcripció de gens mitjançant la unió a llocs específics dins el genoma. Per tant, la caracterització dels llocs d'unió dels diferents factors de transcripció és crucial per tal d’entendre com funciona la regulació gènica. En aquest context, desenvolupar eines computacionals és importantíssim. En aquesta tesi predict redundància entre factors de transcripció de llevat eines fent servir eines basades en homologia i interaccions proteïna-proteïna. Aquesta aproximació va ser automatitzada i incorporada a ModLink+, una eina accessible des d’internet i fàcil d'usar per a inferir el plegament de proteïnes a partir d’homòlegs remots. D'altra banda, descric potencials estadístics fraccionats per a interaccions proteïna-ADN. Finalment presento SHAITAN, una aproximació basada en homologia i potencials estadistics que pot ser utilitzada per a predir els llocs d'unió de factors de transcripció així com per saber quins factors de transcripció són més probables que s’uneixin a una determinada seqüència d'ADN.
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García-García, Javier 1982. "Protein-protein interaction network : management of databases and its applications on the computational study of protein-protein interactions." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/286512.
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The use of protein-protein interaction networks has become crucial due to the emergence of systems biology. The completeness and quality of networks, crucial to understand the biochemical mechanisms underlying a system such as a cell, are still challenging the scientific community. This thesis focuses on the data completeness challenge by the development of flexible tools for biological data management. It presents a database framework, BIANA, in which the integrated access to several information sources tackles this problem by unraveling hidden biological associations. BIANA is used to develop protein-protein interaction inference tools based on sequence similarity and protein-protein interactions. I have applied the approach on Salmonella-host infection, a case study where experimental data is scarce. Finally, I have focused on the integration problem of protein sequence annotation, also addressing the prediction of protein-protein interaction interfaces. I have developed a new evaluation measure to compare the predictive power of interface inference approaches.Les xarxes d'interacció proteïna-proteïna han esdevingut crucials des del naixement de la biologia de sistemes. La integritat i qualitat de les xarxes, que són essencials per entendre els mecanismes subjacents a un sistema com la cèl•lula, segueixen desafiant a la comunitat científica. Aquesta tesi se centra en el repte de la integritat de les dades mitjançant el desenvolupament d'eines flexibles per a la gestió de dades biològiques. Presento BIANA, un paquet informàtic que enfoca aquest problema facilitant l'accés integrat a diverses fonts d'informació. BIANA ha servit per desenvolupar eines de predicció d'interaccions proteïna-proteïna combinant les xarxes amb similitud entre seqüències. He aplicat aquest mètode sobre la infecció per Salmonella-hoste, un cas en el qual les dades experimentals són escasses. Finalment, m'he centrat en la integració associada a l'anotació de seqüències, abordant la predicció d'interfícies d'interacció proteïna-proteïna. Una nova mesura d'avaluació m'ha permès comparar el poder predictiu de diferents mètodes.
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Schnee, Margit. "Protein fragment complementation assay for studying viral protein-protein interactions." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-65582.
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Ruan, Peiying. "Computational Methods for Analyzing Protein Complexes and Protein-Protein Interactions." 京都大学 (Kyoto University), 2015. http://hdl.handle.net/2433/199433.
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Stevenson, Calum. "Database mining studies on protein-peptide and protein-protein interactions." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/7644.
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A major area of interest is the identification of proteins that play a role in hormone dependent cancers and in collaboration with the MRC Centre for Reproductive Health we studied the gonadotropin releasing hormone receptor (GnRH-R). Other targets described in the thesis are the SH3 domain of PSD-95 and the protein BLyS. In order to identify potential inhibitory small molecules we have used a variety of computational data base mining approaches as well as using and developing experimental binding assays. It has become increasingly challenging to evaluate the most representative drug like small molecule compounds when using traditional high throughput screening methods. This thesis assesses the use of in silico tools to probe key protein-protein and protein-peptide interactions. These tools provide a means to identify enriched compound datasets which can be purchased and tested in vitro in a time and cost efficient way. The transmembrane protein GnRH-R provides an interesting opportunity to identify small molecules that could inhibit the binding of its peptide ligand GnRH. This is a challenging project as there are few examples in the literature of drug-like molecules that bind to such protein-peptide interfaces. The first step involved receptor modelling using solved crystal structures of homologous proteins. The model was then validated by developing structure activity relationships for established high affinity ligands. We also performed crystallographic and biophysical studies on the native GnRH decapeptide. Two other protein-protein systems were also examined using the same virtual screening and experimental ligand binding methodology. SH3 domains play an important role in cell signalling and we used the PSD-95 protein as our target for study as a crystal structure has been published. As well as identifying potential ligands we characterised structural properties of PSD-95 fusion proteins and also developed the basis for compound assay. The third system studied was B Lymphocyte Stimulator (BLyS) which is a target for treatment of a number of autoimmune diseases. This presented an interesting target for study as the protein binds to multiple receptors depending on its multimeric state. BLyS protein was characterised using electron microscopy and other biophysical techniques.
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Cao, Zehui. "Designer oligonucleotides for probing dna-protein and protein-protein interactions." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0008333.
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Yu, Chao. "Matrix bound peptides modeling protein-protein interactions." [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969927932.
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Davidson, L. "Protein-protein interactions in GnRH receptor signalling." Thesis, University of Edinburgh, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649167.
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Human embryonic kidney (HEK) 293 cells, stably expressing the rat GnRH receptor were used to investigate the mechanism of ERK activation by GnRH. ERK activation was found to be dependent on cell adhesion to the extracellular matrix, and required an intact actin cytoskeleton. Through the use of specific pharmacological inhibitors and expression of dominant negative cDNA constructs, ERK activation was found to be mediated by the Rho family GTPase Rac1, and the non-receptor tyrosine kinases Src and focal adhesion kinase (FAK). FAK was found to function as a tyrosine phosphorylated scaffold upon which components of the ERK cascade assembled. Having established a role for Src in the activation of ERK, a proteomics study was undertaken to identify novel Src binding proteins that may be involved in the regulation of GnRH receptor signalling. Through a combination of immune-precipitation, two-dimensional gel electrophoresis, and matrix assisted laser desorption ionisation – time of flight mass spectrometry, Src was found to associate with the lipid kinase diacylglycerol kinase zeta (DGKζ). This interaction was found to be required for GnRH to stimulate DGKζ enzyme activity. By phosphorylating the second messenger molecule diacylglycerol to produce phosphatidic acid, DGKζ may play an important role in regulating GnRH receptor signalling. In this thesis, a potential mechanism of ERK activation is described for the GnRH receptor, with Src playing a key role in this pathway. In addition, Src was found to be involved in the activation of DGKζ, and is therefore implicated in the regulation of diacylglycerol signalling. This is the first report of an interaction between Src and DGKζ.
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Walker-Taylor, Alice. "Analysis and prediction of protein-protein interactions." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405881.
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Campbell, M. P. "A bioinformatics approach to protein-protein interactions." Thesis, University of Essex, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426014.
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Nuhu, Mariam. "Protein-protein interactions and aggregation in biotherapeutics." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/proteinprotein-interactions-and-aggregation-in-biotherapeutics(1dba3d89-1474-486c-9eb9-6e21b4616dd9).html.
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Protein aggregation is a frequently cited problem during the development of liquid protein formulations, which is especially problematic since each protein exhibits different aggregation behaviour. Aggregation can be controlled by judicious choice of solution conditions, such as salt and buffer type and concentration, pH, and small molecule additives. However, finding conditions is still a trial and error process. In order to improve formulation development, a fundamental understanding of how excipients impact upon protein aggregation would significantly contribute to the development of stable protein therapeutics. The underlying mechanisms that control effects of excipients on protein behaviour are poorly understood. This dissertation is directed at understanding how excipients alter the conformational and colloidal stability of proteins and the link to aggregation. This knowledge can be used for finding novel ways of either predicting or preventing/inhibiting protein aggregation. Experiments using static and dynamic light scattering, intrinsic fluorescence, turbidity and electrophoretic light scattering were conducted to study the effect of solution conditions such as pH, salt type and concentration on protein aggregation behaviour for three model systems: lysozyme, insulin and a monoclonal antibody. Emphasis is placed on understanding the effects of solution additives on protein-protein interactions and the link to aggregation. This understanding has allowed the rational development of stable formulations with novel additives, such as arginine containing dipeptides and polycations.
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Eckenrode, Sokolowski Tara. "Computational prediction of human protein-protein interactions." Thesis, University of Dundee, 2013. https://discovery.dundee.ac.uk/en/studentTheses/3609a365-dc5c-4347-bca8-a8fc17f76a4d.
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Over the past decade, knowledge of the human genome has grown exponentially. While identifying individual genes and their protein products is crucial, understanding how these entities exist within the context of other molecules within the cell provides valuable insight into their functional significance. In particular, mapping the intricate web of interactions between proteins (or the ‘interactome’), allows for an understanding the roles of individual proteins within specific cellular processes and the potentially negative implications when these processes cannot occur. At the present time, approximately 40,000 binary, protein-protein interactions have been identified in human through low- and high-throughput, lab-based experiments; however, this number represents only a fraction of the estimated 600,000 protein-protein interactions thought to occur. With the high number of potential protein-protein pairing, experimentally testing each possible interaction is a time-consuming and near-impossible task. As a result, several computational methods have been developed to predict probable interactions for experimental verification. Previously, our group developed PIPs, a predictor of protein-protein interactions in human based on a naive Bayesian framework that has undergone two version releases (Scott et al., 2007, McDowall, 2011). In this thesis, a third version of PIPs, PIPs v. 3.0, is described. In addition to an update of the included data, PIPs v. 3.0 contains a new network analysis component, the TransMCL (Z) module, that combines the previously separate Transitive module (and associated EOCT predictor) introduced in version 1.0 and Cluster module (and associated EOCM predictor) introduced in version 2.0. This new module has allowed the two previously separate PIPs predictors to be merged into one method (the EOCZ predictor). In total, the new EOCZ predictor identifies over 500K significant interactions, made up of those predicted by the EOCT and EOCM predictors individually as well as a new set of interactions.Additionally, this thesis describes the development of PIP’NN, a new protein-protein interaction predictor built on a neural network framework with the data incorporated into PIPs. Overall, PIP’NN performs slightly better than the three PIPs predictors on multiple blind tests of varying sizes. PIP’NN identifies both interactions predicted by the three PIPs methods as well as a set of new interactions. As a result, PIP’NN is able to stand on its own as a new predictor of human protein-protein interactions or in conjunction with PIPs as a method to further narrow down the set of predicted interactions. Finally, this thesis describes the practical implementation of PIPs and PIP’NN through collaborations with two groups within the University of Dundee that have identified sets of potential interactions of interest for experimental confirmation. While these interactions have yet to be confirmed, both studies offer a proof of concept of how the predictors can be incorporated into lab-based interaction identification protocols. Additionally, the new PIPs web server will allow outside groups access to the updated PIPs prediction database.Overall, the work described in this thesis has built upon previous work both within and outside of the University of Dundee to further the identification of novel protein-protein interactions in human and increase the understanding of the human interactome.
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Derevyanko, Georgy. "Structure-based algorithms for protein-protein interactions." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENY070/document.
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Les phénotypes de tous les organismes vivants connus sont déterminés par les interactions compliquées entre les protéines produites dans ces organismes. La compréhension des réponses des organismes aux stimuli externes ou internes est basée sur la compréhension des interactions des protéines individuelles et des structures de ses complexes. La prédiction d'un complexe de deux ou plus protéines est le problème du domaine du docking protéine-protéine. Les algorithmes du docking ont habituellement deux étapes majeurs: recherche 6D exhaustive suivi par le scoring. Dans ce travail, nous avons contribués aux deus étapes sus indiquées. Nous avons développés le nouvel algorithme pour la recherche 6D exhaustive, HermiteFit. Cela est basé sur la décomposition des fonctions 3D en base Hermite. Nous avons implémenté cet algorithme dans le programme pour le fitting (l'ajustement des donnés) des cartes de densité électronique de résolution faible. Nous avons montrés qu'il surpasse les algorithmes existants en terme de temps par point tandis qu'il maintient la même précision du modèle sortant. Nous avons aussi développés la nouvelle approche de calculation de la fonction du scoring, qui est basé sur les arguments logique simples et qui évite la calculation ambiguë de l'état de référence. Nous avons comparés cela aux fonctions de scoring existantes avec l'aide du docking protéines-protéines benchmarks bien connues. Enfin, nous avons développés une approche permettant l'inclusion des interactions eau-protéine à la fonction du scoring et nous avons validés notre méthode pendant le CAPRI (Critical Assessment of Protein Interactions) tour 47The phenotype of every known living organism is determined mainly by the complicated interactions between the proteins produced in this organism. Understanding the orchestration of the organismal responses to the external or internal stimuli is based on the understanding of the interactions of individual proteins and their complexes structures. The prediction of a complex of two or more proteins is the problem of the protein-protein docking field. Docking algorithms usually have two major steps: exhaustive 6D rigid-body search followed by the scoring. In this work we made contribution to both of these steps. We developed a novel algorithm for 6D exhaustive search, HermiteFit. It is based on Hermite decomposition of 3D functions into the Hermite basis. We implemented this algorithm in the program for fitting low-resolution electron density maps. We showed that it outperforms existing algorithms in terms of time-per-point while maintaining the same output model accuracy. We also developed a novel approach to computation of a scoring function, which is based on simple logical arguments and avoids an ambiguous computation of the reference state. We compared it to the existing scoring functions on the widely used protein-protein docking benchmarks. Finally, we developed an approach to include water-protein interactions into the scoring functions and validated our method during the Critical Assessment of Protein Interactions round 47
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Banda, Srikanth. "Protein-protein Interactions of Bacterial Topoisomerase I." FIU Digital Commons, 2017. http://digitalcommons.fiu.edu/etd/3378.
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Protein-protein interactions (PPIs) are essential features of cellular processes including DNA replication, transcription, translation, recombination, and repair. In my study, the protein interactions of bacterial DNA topoisomerase I, an essential enzyme, were investigated. The topoisomerase I in bacteria relaxes excess negative supercoiling on DNA and maintains genomic stability. Investigating the PPI network of DNA topoisomerase I can further our understanding of the various functional roles of this enzyme. My study is focused on topoisomerase I of Escherichia coli and Mycobacterium smegmatis. Firstly, we have explored the biochemical mechanisms for an interaction between RNA Polymerase, and topoisomerase I in E. coli. Molecular docking and molecular dynamic simulations have predicted that the interactions are mediated through electrostatic, and hydrogen bonding. The predicted Lysine residues (K627, K664) of topoisomerase I that are involved in the electrostatic interactions were mutated to Alanine, and its effect on the binding efficiency with RNA polymerase was reported. In a separate study, PPI partners of topoisomerase I in mycobacteria were identified. Knowledge gained from the study can provide valuable insights into the physiological functions of a validated drug target, DNA topoisomerase I, in pathogenic mycobacteria. Co-immunoprecipitation and pull-down assays were coupled to mass spectrometry for identification of the protein partners of mycobacterial topoisomerase I. The study has identified RNA polymerase, and putative helicases (DEAD/DEAH BOX helicases) as potential protein partners of mycobacterial topoisomerase I. My results indicated that the tail region of the CTD-topoisomerase I was required for direct physical interaction with the RNAP beta’ subunit. My studies have also verified the physiological relevance of the topoisomerase I - RNA polymerase interactions for survival under antibiotic, and oxidative stress. Lastly, I report a direct physical interaction between E. coli topoisomerase I and RecA by pull-down assays. Previous studies have shown that RecA, a DNA repair protein, can stimulate the relaxation activity of E. coli topoisomerase I. Our new results showed that the stimulatory effect can be attributed to the physical interaction of topoisomerase I with RecA.
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Anscombe, Elizabeth. "Targeting protein-protein interactions for cancer therapy." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:6155f526-5e56-454c-819d-9510fb6f9e02.
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Protein-protein interactions (PPIs) are key drug targets and recent breakthroughs in this area are providing insight into the types of molecules needed to selectively and potently inhibit a target traditionally seen as untractable. The rules that have been used to design classic substratecompetitive drugs (for example Lipinski's rule of five) may not apply in this new field in the same way. Here I present work performed in three systems that are well-validated drug targets for oncogenesis: the CDK2/cyclin A complex, the PLK1 Polobox domain and MDM2. In each case the site of the protein-protein interaction is defined and understood and the rationale for pharmaceutical intervention is clear. I use these as a model system to evaluate the characteristics of drugs that target protein-protein interaction sites and present work on the development of inhibitors as potential leads for subsequent drug development. In Chapter 1 I introduce the problems, challenges and rewards of PPI drug development; in Chapter 2 I present co-crystal structures of MDM2 with isoindolinone inhibitors; in Chapter 3 I detail attempts to co-crystallise the Plk1 Polobox with inhibitors and screen potential inhibitors; in Chapter 4 I present the results of screening to identify inhibitors of Cyclin A recruitment; and in Chapter 5 I discuss other strategies for inhibition of the CDK2/cyclin A complex, including results with a covalent inhibitor. Through these projects I have been able to demonstrate the wide applicability of the PPI inhibition approach, identify key features of drugs able to inhibit PPIs and contribute to drug design in each system.
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Lewis, Anna Claire Felicity. "Communities and homology in protein-protein interactions." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558460.
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Knowledge of protein sequences has exploded, but knowledge of protein function is needed to make use of sequence information, and this lags behind. A protein's function must be understood in context and part of this is the network of interactions between proteins. What are the relationships between protein function and the structure of the interaction network? In the first part of my thesis, I investigate the functional relevance of clusters, or communities, of proteins in the yeast protein interaction network. Communities are candidates for biological modules. The work I present is the first to systematically investigate this structure at multiple scales in such networks. I develop novel tests to assess whether communities are functionally homogeneous, and demonstrate that almost every protein is found in a functionally homogeneous community at some scale. The evolution of protein sequences IS well-studied, but comparatively little is known about the evolution of protein function. Such knowledge is needed to un- derstand when it is appropriate to annotate newly sequenced proteins by transferring functional information from homologs-i.e. evolutionarily related proteins. In the sec- ond part of my thesis, I assess the success of transferring protein-protein interactions across species and use this to estimate the rate at which interactions are lost in evolu- tion. At levels of sequence similarity associated with functional annotation transfer, I demonstrate that protein-protein interaction transfer is unreliable. The relevance of community structure for understanding protein function and the low conservation of individual interactions, suggests a possible role for communities in the evolution of cellular function. I discuss this possibility in my conclusions.
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DeNunzio, Nicholas Joseph. "Biophysical methods for analyzing protein-protein interactions." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12343.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Protein-protein interactions are integral to myriad molecular biological processes as they transfer information between molecules to effect a variety of goals. These include complex formation to activate gene transcription, serial interactions in signal transduction cascades, and one-time receptor-ligand or enzyme-substrate binding. Better understanding these interactions can therefore inform our view of larger biological frameworks and may be accomplished via direct visualization studies using structural and microscopy-based platforms. Using x-ray crystallography, the complex formed by the catalytic light chain of the Clostridium botulinum Serotype A neurotoxin (BoNT/A-LC) and its physiological substrate, synaptosomal-associated protein 25 (SNAP-25), has been examined to aid future inhibitor development. While small molecule and peptidic active site directed inhibitors have been published for this zinc-dependent protease, additional binding sites outside this region may exist given the extensive binding interface between these proteins. To identify these putative sites we conducted a computational analysis of the hydration structure of BoNT/A-LC across crystal structures to identify water molecules that are highly conserved as well as those that are more easily displaced, particularly when the BoNT/A-LC:SNAP-25 complex is formed. Results of these analyses are presented, including implications for de novo inhibitor design and extending previously established chemical scaffolds. In contrast, lower-resolution time-resolved luminescence microscopy (TRLM) was employed to develop a novel probe for imaging the receptor-ligand complex formed by interleukin-1 beta (IL1β) or epidermal growth factor (EGF) and their respective receptors. While a plethora of molecular tags exist for cellular localization studies, they often rely on chemically ligating an exogenous fluorophore to a protein target or endogenously expressing large protein-based tags (e.g. green fluorescent protein) in tandem with the protein to be tracked. We aimed to develop a compact genetically encoded tag that may be detected via in vitro and in cellula visualization studies using TRLM to measure long- lived luminescence while bypassing the epifluorescence that can be observed when irradiating biological specimens. Provided a sufficient concentration of LBT-tagged ligand is localized along a surface, the luminescent signal can be detected exclusive of epifluorescence. Future efforts to improve the physicochemical properties of the LBT and the imaging platform characteristics are discussed.
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Vangone, Anna. "In silico study of protein-protein interactions." Doctoral thesis, Universita degli studi di Salerno, 2013. http://hdl.handle.net/10556/1164.
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2011 - 2012Protein-protein interactions are at the basis of many of the most important molecular processes in the cell, which explains the constantly growing interest within the scientific community for the structural characterization of protein complexes.1 However, experimental knowledge of the 3D structure of the great majority of such complexes is missing, and this spurred their accurate prediction through molecular docking simulations, one of the major challenges in the field of structural computational biology and bioinformatics.2,3 My PhD work aims to contribute to the field, by providing novel computational instruments and giving useful insight on specific case studies in the field. In particular, in the first part of my PhD thesis, I present novel methods I developed: i) for analysing and comparing the 3D structure of protein complexes, to immediately extract useful information on the interaction based on a contact map visualization (COCOMAPS4 web tool, Chapter 2), and ii) for analysing a set of multiple docking solutions, to single out the key inter-residue contacts and to distinguish native-like solutions from the incorrect ones (CONS-COCOMAPS5 web tool and CONS-RANK program, Chapter 3 and 4, respectively). In the second part of the thesis, these methods have been applied, in combination with classical state-of-art computational biology techniques, to predict and analyse the binding mode in real biological systems, related to particular diseases. This part of the work has been afforded in collaboration with experimental groups, to take advantage of specific biological information on the systems under study. In particular, the interaction between proteins involved in the autoimmune response in celiac disease6,7 (Chapters 5 and 6) has been studied in collaboration with the group directed by Prof. Sblattero, University of Piemonte Orientale (Italy) and the group directed by Prof. Esposito, University of Salerno (Italy). In addition, recognition properties of 3 the FXa enzymatic system8 has been studied through dynamic characterization of a FXa pathogenic mutant that causes problems in the blood coagulation cascade (Chapter 7). This study has been performed in collaboration with the group directed by Prof. De Cristofaro, Catholic University School of Medicine, Rome (Italy) and the group directed by Prof. Peyvandi, Ospedale Maggiore Policlinico and Università degli Studi di Milano (Italy)... [edited by author]
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Valstar, Ank. "Protein-surfactant interactions." Doctoral thesis, Uppsala University, Department of Physical Chemistry, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1070.
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Protein-surfactant interactions in aqueous media have been investigated. The globular proteins lysozyme and bovine serum albumin (BSA) served as model proteins. Several ionic and non-ionic surfactants were used.
Fluorescence probe measurements showed that at low sodium dodecyl sulfate (SDS) concentration (< 0.1 M) one micelle-like SDS cluster is bound to lysozyme. From dynamic light scattering (DLS) results it was observed that lysozyme in the complex does not correspond to the fully unfolded protein. At high SDS concentration (> 0.1 M) one compact and one more extended lysozyme-SDS complex coexist.
The influence of surfactant alkyl chain length and headgroup on BSA-surfactant complex formation was investigated. In these studies, binding isotherms were determined by nuclear magnetic resonance (NMR), DLS was used to measure the hydrodynamic radii of the complexes and the size of the micelle-like aggregates on BSA was determined using fluorescence probe methods.
It was observed from fluorescence measurements that the number of bound SDS molecules does not depend on the presence of the disulfide bridges. Reduced proteins wrap more efficiently around the micelle-like structures, resulting in somewhat smaller complexes, as observed with DLS.
Concentrated BSA-SDS solutions and the corresponding heat-set gels were investigated using DLS and fluorescence probe methods. Correlation lengths in the gel were determined and it was concluded that SDS forms micelle-like aggregates on BSA in concentrated solution and gel phase. The gel region in the ternary phase diagram BSA-SDS-3.1 mM NaN3 has been determined at room temperature.
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Bartzoka, Vasiliki. "Silicone-protein interactions." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape3/PQDD_0035/NQ66252.pdf.
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Moothoo, Davina Noelle. "Protein-carbohydrate interactions." Thesis, University of St Andrews, 1998. http://hdl.handle.net/10023/14528.
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Carbohydrates are ubiquitous in nature and have become the focus of much scientific investigation. The proteins which recognise carbohydrates have become widely used in the areas of cell and molecular biology. Protein - carbohydrate interactions have been probed by theoretical, structural and thermodynamic techniques. The lectins are a class of carbohydrate binding proteins which bind carbohydrates through non covalent interactions such as hydrogen bonds and van der Waals interactions. In addition to these interactions, other factors play an important role in determining affinity such as carbohydrate conformation, solvent reorganisation and changes in the protein binding site. The legume lectin concanavalin A specifically recognises mannose and glucose terminal residues. The thermodynamics of concanavalin A binding to carbohydrates has been well documented. Concanavalin A binds the core trimannoside and pentasaccharide of the biantennary glycan found on mammalian cell surfaces with a high affinity. This thesis describes the structural basis of carbohydrate binding by con A, through the interpretation of crystal structures of concanavalin A bound with α1-2 mannobiose, methyl α1-2 mannobioside, the core pentasaccharide of the biantennary glycan and fructose. The structural information obtained from these structures is related to thermodynamic information available and unravels the importance of the role played by carbohydrate conformation, solvent reorganisation and statistical population of ligand in determining affinity. This work helps to develop an understanding of the physical basis of carbohydrate recognition.
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Chen, Huiling Zhou Huan Xiang Ferrone Frank A. "Prediction of protein structures and protein-protein interactions : a bioinformatics approach /." Philadelphia, Pa. : Drexel University, 2005. http://dspace.library.drexel.edu/handle/1860/481.
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Worthington, Andrew Schuyler. "Chemoenzymatic investigations of protein-protein interactions in carrier protein-mediated biosynthesis." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3338769.
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Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed January 9, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Quinlan, Robert Jason. "An investigation into the role of protein-ligand interactions on obligate and transient protein-protein interactions." Texas A&M University, 2004. http://hdl.handle.net/1969.1/1430.
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Protein-ligand and protein-protein interactions are critical to cellular function. Most cellular metabolic and signal tranduction pathways are influenced by these interactions, consequently molecular level understanding of these associations is an important area of biochemical research. We have examined the thermodynamics of several protein-protein associations and the protein-ligand interactions that mediate them.
Using Fluorescence Correlation Spectroscopy, we have examined the putative interaction between pig heart malate dehydrogenase (MDH) and citrate synthase (CTS). We demonstrate a specific, low-affinity interaction between these enzymes. The association is highly polyethylene glycol (PEG)-dependent, and at high concentrations of NaCl or PEG, non-specific aggregates are formed. We demonstrate that oxaloacetate, the intermediate common to both CTS and MDH, induces the association at concentrations below the Km of CTS, suggesting that the open conformation of CTS is involved in the association.
Using several biophysical techniques, we have examined the subunit associations of B. stearothermophilus phosphofructokinase (PFK). We demonstrate that the inhibitor bound conformation of the enzyme has reduced subunit affinity. The kinetics and thermodynamics of the phosphoenolpyrvuate (PEP)-induced dissociation of PFK have been quantified. Binding substrate, fructose-6-phosphate (F6P), stabilizes the enzyme to inhibitor-induced dissociation by 132-fold. These data suggest that subunit associations may play a role in the allosteric inhibition of PFK by PEP.
The thermodynamics of the protein-ligand associations and allosteric inhibition of E. coli phosphofructokinase have been examined using intrinsic fluorescence and hydrostatic pressure. Both ligand-binding affinity and PEP inhibition are diminished by pressure, whereas substrate-binding affinity for inhibitor-bound enzyme is pressure-insensitive. Larger entropic than enthalpic changes with pressure lead to the overall reduction in free energies.
Using a fluorescence-based assay, we have developed a series of baroresistant buffer mixtures. By combining a buffer with acid dissociation of negative volume with a buffer of positive volume, a pressure-resistant mixture is produced. Alteration of the molar ratio of the two component buffers yields mixtures that are pressure-insensitive at pH values around neutrality.
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Giesecke, Astrid. "Protein-protein interactions mediated by Cys2His2 zinc-fingers." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=981809715.
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Ahmed, Ibrahim H. I. "Computational prediction of host-pathogen protein-protein interactions." University of the Western Cape, 2017. http://hdl.handle.net/11394/5652.
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Philosophiae Doctor - PhDSupervised machine learning approaches have been applied successfully to the prediction of protein-protein interactions (PPIs) within a single organism, i.e., intra-species predictions. However, because of the absence of large amounts of experimentally validated PPIs data for training and testing, fewer studies have successfully applied these techniques to host-pathogen PPI, i.e., inter-species comparisons. Among the host-pathogen studies, most of them have focused on human-virus interactions and specifically human-HIV PPI data. Additional improvements to machine learning techniques and feature sets are important to improve the classification accuracy for host-pathogen protein-protein interactions prediction. The primary aim of this bioinformatics thesis was to develop a binary classifier with an appropriate feature set for host-pathogen protein-protein interaction prediction using published human-Hepatitis C virus PPI, and to test the model on available host-pathogen data for human-Bacillus anthracis PPI. Twelve different feature sets were compared to find the optimal set. The feature selection process reveals that our novel quadruple feature (a subsequence of four consecutive amino acid) combined with sequence similarity and human interactome network properties (such as degree, cluster coefficient, and betweenness centrality) were the best set. The optimal feature set outperformed those in the relevant published material, giving 95.9% sensitivity, 91.6% specificity and 89.0% accuracy. Using our optimal features set, we developed a neural network model to predict PPI between human-Mycobacterium tuberculosis. The strategy is to develop a model trained with intra-species PPI data and extend it to inter-species prediction. However, the lack of experimentally validated PPI data between human-Mycobacterium tuberculosis (Mtuberculosis), leads us to first assess the feasibility of using validated intra-species PPI data to build a model for inter-species PPI. In this model we used human intra-species PPI combined with Bacillus anthracis intra-species data to develop a binary classification model and extend the model for human-Bacillus anthracis inter-species prediction. Thus, we test our hypotheses on known human-Bacillus anthracis PPI data and the result shows good performance with 89.0% as average accuracy. The same approach was extended to the prediction of PPI between human-Mycobacterium tuberculosis. The predicted human-M-tuberculosis PPI data were further validated using functional enrichment of experimentally verified secretory proteins in M-tuberculosis, cellular compartment analysis and pathway enrichment analysis. Results show that five of the M-tuberculosis secretory proteins within an infected host macrophage that correspond to the mycobacterial virulent strain H37Rv were extracted from the human-M- tuberculosis PPI dataset predicted by our model. Finally, a web server was created to predict PPIs between human and Mycobacterium tuberculosis which is available online at URL:http://hppredict.sanbi.ac.za. In summary, the concepts, techniques and technologies developed as part of this thesis have the potential to contribute not only to the understanding PPI analysis between human and Mycobacterium tuberculosis, but can be extended to other pathogens. Further materials related to this study are available at ftp://ftp.sanbi.ac.za/machine learning.
National Research Foundation (NRF) and SANBI
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Thelin, William R. Milgram Sharon L. "The regulation of CFTR by protein-protein interactions." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,318.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell and Developmental Biology." Discipline: Cell and Developmental Biology; Department/School: Medicine.
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Ansari, Sam. "Analysis of protein-protein interactions : a computational approach /." Saarbrücken : VDM Verl. Dr. Müller, 2007. http://deposit.d-nb.de/cgi-bin/dokserv?id=2992987&prov=M&dok_var=1&dok_ext=htm.
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Gruber, Jan. "Practical and theoretical studies of protein-protein interactions." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432287.
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Ho, J. G. S. "An investigation of protein-protein interactions during renaturation." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604100.
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The aim of the research presented in this thesis is to determine the applicability of measuring protein-protein interactions (the second virial coefficient) to protein renaturation (refolding). As shown subsequently in this thesis, the second virial coefficient provides an experimentally accessible link between empirical observations with molecular and thermodynamic insight into protein aggregation during renaturation. This thesis is the first instance that light scattering has been used to probe protein-protein interactions during the renaturation, and describes the theory, development and validation of this technique. Using this new approach, four major themes on protein-protein interactions and protein renaturation are explored. The first theme is the influence of surface properties of proteins (hydration and surface hydrophobicity) and how they affect protein-protein interactions. Secondly, a quantitative method for assessing both the sign and magnitude of protein-protein interactions in relation to empirical observations of protein aggregation and protein solubility are presented. This subsequently leads to the issue of the impact of protein-protein interactions and water structure on renaturation. A simple technique to assess water structure conducive to protein renaturation is also introduced. The final theme is to present the measure of second virial coefficients as a simple metric for assessing the propensity of inclusion body proteins to aggregate during renaturation. A variety of inclusion bodies are screened and relationships between protein molecular weight, hydropathicity, and fractional yield are presented. The key outcome of this thesis is the demonstration of the utility of the second virial coefficient as a tool to rationally screen renaturation conditions for new proteins. It will help our understanding of why certain conditions promote renaturation in preference to aggregation. Importantly, this technique provides a useful tool for determining refolding strategy, provides a link between empirical practice and fundamental thermodynamics and demonstrates an initial relationship between protein sequence and structure for the protein production/refolding process.
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Han, J. H. "Structure, function and evolution of protein-protein interactions." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603640.
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In this thesis we are concerned with structural, functional and evolutionary aspects of protein interactions. Chapter 1 introduces background information including important concepts in protein structural classification and gene regulation. It provides an overview of methods and databases that are pertinent to this thesis. Most proteins in genomes are the product of recombination of two or more proteins. Previous studies of domain combinations have shown that homologous combinations of domains tend to strongly conserve their N-to-C terminal order of domains as well as their 3-dimensional orientation. In Chapter 2, in order to investigate the extent of this conservation and the nature of domain-domain interactions that result in divergent domain geometry, homologous proteins with 128 different combinations are examined. We demonstrate that about two thirds of combinations conserve their domain geometry and divergent geometry results form five different types of domain interfaces. Chapter 3 extends concepts applied in the analysis of domain geometry to discuss the implications of domain-domain interactions to the folding of multi-domain proteins. By analysing all known multi-domain proteins that have been subjected to experimental folding studies, a correlation between the nature of domain interfaces and folding interdependency of domains is described. In Chapter 4 a set of gene regulatory protein-protein interactions formed by over one thousand mammalian proteins is analysed. Here, the concept of protein families defined by the ordered domain content of proteins used in previous chapters is employed in order to extract families of homologous interactions. In addition a functional classification of gene regulatory proteins is outlined. Chapter 5 summarises the novel results presented in this thesis and discusses their relevance in the context of other studies.
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Bradford, James Richard. "Studies on the prediction of protein-protein interactions." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414574.
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DiÌaz, Maria Dolores FernaÌndez. "Effects of high pressure on protein protein interactions." Thesis, University of Reading, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270415.
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Rowell, Philip Lee. "Protein-protein interactions of the BCL-2 family." Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/20769/.
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The BCL-2 family of proteins are important regulators of mitochondrial apoptosis, comprising both pro- and anti-apoptotic members that interact with one another at the mitochondrial outer membrane to determine cellular fate. Dysregulation of their activities in the cell is implicated in many forms of cancer; the development of molecules able to mimic and modulate their interactions is thus highly desirable and has been the subject of a great deal of research effort. The use of techniques including structure based design and peptidomimetic approaches has produced some notable successes in this area, but few have successfully transitioned from laboratory to clinic, and the search for more and better ways to develop such molecules continues. In this thesis, I present a novel approach to identifying binding partners for BCL-2 proteins, which uses phage display experiments and the production of non-antibody scaffold proteins called Affimers. Five BCL-2 family proteins were selected as targets for study, comprising a good cross section of proand anti-apoptotic members. In the following chapters, I first describe the work undertaken to purify and characterise these target proteins, then detail the work done to identify and purify Affimer binding partners for each of them. Finally, I report on structural studies carried out to explore the mechanism by which BAX, a pro-apoptotic family member, forms death inducing oligomers. Taken together, the results of this project lay the foundations for further structural studies of BAX oligomerisation, and demonstrate that the use of phage display to generate selectively binding non-antibody scaffold proteins can provide useful additions to the existing array of BCL2 family interacting molecules.
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Hadje, Georgiou Kathy. "Approaches towards the inhibition of protein-protein interactions." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709214.
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Tan, Wu Meng. "Protein-protein interactions in the Fanconi anaemia pathway." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616054.
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