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1
Rajbanshi, Arbin. "Supramolecular interactions from small-molecule selectivity to molecular capsules". Diss., Manhattan, Kan. : Kansas State University, 2010. http://hdl.handle.net/2097/3879.
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Bouanga, Boudiombo Jacky Sorrel. "Molecular selectivity by host-guest methods". Doctoral thesis, Faculty of Science, 2021. http://hdl.handle.net/11427/33667.
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The Host-Guest inclusion crystallization method has long been used for the separation of closely related compounds. Especially for the separation of isomers which presented difficulties in techniques like distillation or chromatography. In this study, different host systems were used to separate isomers of trimethoxybenzenes, lutidines, methylacetophenones and xylenols. Isomers are compounds with the same molecular formula but different arrangement of their atoms. They are often produced as mixtures when synthesised in large quantities by various industries and are more valuable as purified single components. Thus, it is important to separate them into their individual components. The process of Host-Guest method is dependent on the phenomenon of molecular recognition between the host and guest molecules, and this, in turn, relies on the sum of non-bonded, secondary interactions which impinge on the final crystalline product. This is especially the case for enantiomers which are isomers with the same boiling points and melting point. However, enantiomers differ by their ability to diffract polarised light. Although countless methods have been used for their separation, one method that has been proven to be certainly successful on this path was the “family method”. The “Dutch resolution method” or the “family method” makes use of the crystallization technique by mixing similar host compounds to separate enantiomers. However, the improvement of the end results was not understood. In fact, the whole process has been done just on results and no analysis of the actual activity occurring at the molecular level was investigated. In this research, the Host-Guest chemistry method was applied with the aim of separating several isomers compounds in the intention of understanding the selectivity characteristics of a particular host. For the purpose of the analysis, structural isomers with close boiling points were selected. Competition experiments were set to survey which of the isomers were a better fit for a particular host. After analysis of the different crystal material obtained from crystallization experiments with NMR techniques, various trends were observed. X-Ray crystallography was employed to elucidate the crystal structures of the different compound formed by Host-Guest chemistry. The new complexes were further analysed by thermal analysis (TGA, DSC), kinetics of desolvation, Hirshfeld surface analysis, and activation energy of desolvation-analysis techniques. During the separation of the trimethoxybenzene (TMB) isomers, cholic acid and deoxycholic acid' hosts were used in chapter 3. It was found that each host separated the isomers differently. That was independent of the closeness of their molecular structures. The difference in selectivity was attributed to the arrangement of each host in the structure obtained with the guest compounds. Separation of lutidines was carried out in chapters 4 and 5. The first separation consisted of the study of the fifteen pairwise combinations of the isomers with 3,3′-bis(9-hydroxy-9- fluorenyl)2−2′- binaphthyl which is presented in chapter 4. The second analysis was carried out with host 2,2'bis(1-hydroxy-4,5-dihydro-2,3:6,7-dibenzocycloheptatrien-1-yl)-biphenyl. Nevertheless, both hosts preferred 3,4-lutidine. Four additional hosts were used to simulate the “Dutch resolution method” in chapter 5. Further analysis of torsion angles was performed over the five hosts for the complexes formed with 2,4-lutidine and 3,5-lutidine. The host characterized by unbridged phenyl moieties and the one characterized by bulky tert-butyl groups was found to prefer 3,5-lutidine. In chapter 6, deoxycholic acid resolved the 2-methylcyclohexanone (2MCH) but not 3- methylcyclohexanone (3MCH) during the separation of methylcyclohexanone isomers. However, during the competition experiment, it was found that when 2MCH was mixed with 3MCH, the latter was resolved as an S-enantiomer. Kinetics of desolvation studied resulted in the determination of the activation energies of the Host-Guest complexes and was like the trend observed by 1H NMR analysis. Chapter 7 was focused on the synergistic effect of mixed hosts system. This was to emphasize the impact that a mixture of compounds with similar structural composition may provide. Competition experiments were done with the 15 pairs of xylenol isomers with 4,4'- isopropylidene Bisphenol. Three of these pairs were selected for further analysis with two similar bisphenol hosts. One interesting structure was obtained with 4,4-isopropylidene Bisphenol and 4,4'-(9-Fluorenylidene) Bisphenol with a guest mixture. This is an unusual result as crystal structures comprising two hosts with two guests are rare.
3
Fransson, Linda. "Molecular modelling - understanding and prediction of enzyme selectivity". Licentiate thesis, KTH, School of Biotechnology (BIO), 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-10532.
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Molecular modelling strategies for evaluation of enzyme selectivity wereinvestigated with a focus on principles of how molecular interactionscould be evaluated to provide information about selectivity. Althoughmolecular modelling provides tools for evaluation of geometrical andenergy features of molecular systems, no general strategies for evaluationof enzyme selectivity exist. Geometrical analyses can be based uponinspection and reasoning about molecular interactions, which provide aneasily accessible way to gain information, but suffer from the risk of biasput in by the modeller. They can also be based on geometrical features ofmolecular interactions such as bond lengths and hydrogen-bond formation.Energy analyses are appealing for their modeller independenceand for the possibility to predict not only stereopreference, but also itsmagnitude.In this thesis, four examples of enantio- or regioselective serinehydrolase-catalysed reaction systems are presented together with developedmodelling protocols for explanation, prediction or enhancement ofselectivity. Geometrical as well as energy-based methodology were used,and provided an understanding of the structural basis of enzymeselectivity. In total, the protocols were successful in making qualitative explanationsand predictions of stereoselectivity, although quantitative determinationswere not achieved.
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Heung, Yen Ming Mary. "Molecular selectivity of phospholipase D in granulocyte function". Thesis, University of Southampton, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241935.
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Maughfling, Edward John Rosewarne. "Molecular basis for the ligand selectivity of bombesin receptors". Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.625098.
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Bauer, Paul. "Computational modelling of enzyme selectivity". Doctoral thesis, Uppsala universitet, Struktur- och molekylärbiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-326108.
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Enantioselective reactions are one of the ways to produce pure chiral compounds. Understanding the basis of this selectivity makes it possible to guide enzyme design towards more efficient catalysts. One approach to study enzymes involved in chiral chemistry is through the use of computational models that are able to simulate the chemical reaction taking place. The potato epoxide hydrolase is one enzyme that is known to be both highly enantioselective, while still being robust upon mutation of residues to change substrate scope. The enzyme was used to investigate the epoxide hydrolysis mechanism for a number of different substrates, using the EVB approach to the reaction both in solution and in several enzyme variants. In addition to this, work has been performed on new ways of performing simulations of divalent transition metals, as well as development of new simulation software.
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Erlenbach, Isolde. "The molecular basis of V2 vasopressin receptor-G protein coupling selectivity". [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963474448.
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Kröger, Wendy Lee. "A molecular basis for the C-domain selectivity of angiotensin-converting enzyme". Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3134.
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Kroger, W. "A Molecular Basis for the C-Domain Selectivity of Angiotensin-Converting Enzyme". Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3135.
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Angiotensin-Converting Enzyme (ACE) plays an essential role in blood pressure regulationand ACE inhibitors are widely used to treat cardiovascular disease. Two isoforms exist,somatic ACE (sACE) consisting of two homologous domains, N- and C-domain, and testisACE (tACE), corresponding to the C-domain of sACE. Despite a high degree of sequenceidentity, these two domains display marked differences in substrate and inhibitor specificity.Furthermore, the C-domain of ACE has been implicated to play a dominant role in bloodpressure control. It has therefore been suggested that development of ACE inhibitortreatments that selectively block the C-domain will result in decreased side-effects comparedto current therapies. Analysis of three-dimensional structures of tACE in complex withdomain-specific inhibitors has enabled the identification of key active-site residues potentiallyplaying a role in domain selectivity. To investigate the contribution of such residues, a seriesof C-domain mutants was generated containing single and multiple N-domain active-sitesubstitutions. These constructs were used to characterise specific interactions using domainselectiveinhibitors and fluorogenic peptides. Mutants tested with the fluorogenic peptidesdisplayed minimal, if any, acquisition of N-domain-like catalytic properties. Of the singlemutations, S2 (F391Y, tACE numbering) and S1 (V518T) pocket substitutions caused thelargest decreases in affinity for the C-selective phosphinic inhibitor RXPA380 (34-fold) andketo-ACE derivatives (14-26 fold), respectively. The V379S mutation caused an unexpectedincrease in affinity (2-10 fold) for C-selective inhibitors containing a P2’ Trp that could beexplained by the formation of a water-mediated hydrogen bond interaction resulting fromrearrangement of inhibitor and protein side-chains within the S2’ pocket. Multiple mutantscontaining an N-domain-like S2’ pocket combined with the S2 F391Y substitution (S2’F)caused the most notable shift in Ki from that of tACE for the highly selective phosphinicinhibitors, RXPA380 (Ki’s tACE = 69 nM; S2’F = 5300 nM) and N-specific RXP407 (Ki’stACE = 2800 nM; S2’F Ki = 16.1 nM). This work identifies key residues contributing to thedomain selectivity of ACE, and highlights the complex combination of effects involved in thisphenomenon. Furthermore, it provides useful insight for the further design of domainselectiveinhibitors.
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Blgacim, Nuria. "Molecular Control of the δ-opioid Receptor Signaling and Functional Selectivity by Sodium". Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37806.
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Accumulating evidence suggests a prominent role of the arrestin-dependent signaling pathway in triggering most of the deleterious side effects observed using δ-OR targeting drugs. Numerous small molecules targeting the δ-OR receptors have been developed but their pharmacological properties, including their functional selectivity, have been poorly characterized. The absence of functionally selective opioid drugs, and the lack of knowledge of the pharmacological profile and signaling properties of the δ-OR receptor, limits its therapeutic exploitation. The development of functionally selective modulator toward the canonical G protein pathway could importantly increase the therapeutic potential of this receptor while decreasing its deleterious effects. An approach to fine-tune the functional selectivity of a GPCR is by using allosteric modulators. These allosteric modulators would reduce problems associated with drugs targeting the orthosteric site by not chronically activating the receptor. The overall goal of the proposed research is to study the molecular mechanism by which sodium-channel inhibitors allosterically regulates the delta opioid receptor (δ-OR) signaling and functional selectivity. Additionally, the signaling features of the δ-OR signal transduction triggered by biased receptor activation have been investigated. A combination of approaches, including functional studies, molecular modeling and mutagenesis, were used to study the general mechanism underlying the activation and tuning of the δ-OR signal transduction behavior. Thus, this work suggests the druggability of the allosteric sodium pocket by using sodium channel inhibitors. The current research represent discovery of two different allosteric profiles for the β-arrestin recruitment and one allosteric profile for the G-protein pathway at activated DOR and would serve as scaffold for further refinement of modulators with the desired pharmacological profile.
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Blockley, Alix Dawn. "Investigating the molecular basis of resistance and pyrethroid selectivity at acarine sodium channels". Thesis, Birkbeck (University of London), 2017. http://bbktheses.da.ulcc.ac.uk/252/.
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Many acarine (tick and mite) species are ectoparasites of humans, livestock and domestic pets, where they spread disease and impact adversely on health. They are normally controlled through the application of acaricides; however, the prolonged use of individual compounds has resulted in many species developing resistance to specific pesticides. This thesis describes investigations into the molecular properties that determine the resistance to and selectivity of pyrethroids, an important class of pesticides that act on the voltage-gated sodium channels (VGSCs) of arthropod neurons. Comparison of insect and acarine VGSC sequences, coupled with molecular modelling studies, have identified a residue at amino-acid position 933 (M. domestica numbering) found within a putative pyrethroid binding pocket that may contribute to a greater selectivity of pyrethroids with comparatively larger halogenated groups for acarine VGSCs compared to those of insects. This is due to the presence of a smaller glycine residue at position 933 in acarine channels, compared to a cysteine residue in insect channels, which may enhance the binding of such pyrethroids (O'Reilly et al., 2014). This model is supported by the findings of Jonsson et al 2010, that R. microplus cattle ticks carrying the amino acid substitution G933V, are resistant to the pyrethroid flumethrin, which has a comparatively larger halogenated group, but not the pyrethroid cypermethrin, which has a comparatively smaller halogenated group. Work in this thesis describes progress made in the investigation of such specificity; involving sequencing studies, two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes involving insect and acarine VGSCs, and whole arthropod bioassays. While this work cannot conclusively disprove the model proposed by O’Reilly et al 2014, it suggests that the mechanisms of selectivity for pyrethroids in arthropods may involve the interplay of several factors, rather than being solely based upon structural variations in their VGSCs.
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Hermit, Mette Brunsgaard. "Molecular pharmacology of metabotropic glutamate receptors : focus on group III and subtype selectivity /". [Kbh.] : Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2004. http://www.dfh.dk/phd/defences/mettehermit.htm.
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Lee, Kyoungmi. "DEVELOPMENT OF PROTEIN-IMPRINTED POLYSILOXANE BIOMATERIALS: PROTEIN SELECTIVITY AND CELLULAR RESPONSES". Lexington, Ky. : [University of Kentucky Libraries], 2005. http://lib.uky.edu/ETD/ukybien2005t00373/Thesis.pdf.
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Thesis (M.S.)--University of Kentucky, 2005.Title from document title page (viewed on January 19, 2006). Document formatted into pages; contains: viii, 59 p. : ill. (some col.). Includes abstract and vita. Includes bibliographical references (p. 53-58).
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Zaidi, Saheem. "Understanding ligand binding, selectivity and functions on the G protein-coupled receptors: A molecular modeling approach". VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/596.
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The assessment of target protein molecular structure provides a distinct advantage in the rational drug design process. The increasing number of available G protein-coupled receptor crystal structures has enabled utilization of a varied number of computational approaches for understanding the ligand-receptor interactions, ligand selectivity and even receptor response upon ligand binding. The following dissertation examines the results from three different projects with varied objectives – i) structural modeling of human C-C chemokine receptor type 5 (CCR5) and assessment of the ligand binding pocket of the receptor, ii) assessment of the selectivity profile of naltrexone derivatives on the three opioid receptors (μ-opioid, κ-opioid, δ-opioid) with an aim towards designing selective μ-opioid receptor antagonists, and iii) structural modeling of the ‘active’ state conformation of the κ-opioid receptor in response to agonist binding and determination of a plausible molecular mechanism involved in activation ‘switch’ of the κ-opioid receptor. In absence of a crystal-based molecular structure of CCR5, a homology model of the receptor was built and the ligand binding pocket was validated. On the basis of evaluation of the ligand-receptor interactions on the validated binding pocket, structural and chemical modifications to anibamine, a natural plant product, were proposed to enhance its receptor binding. The selectivity of naltrexone (a universal antagonist) was assessed with respect to the three opioid receptors by employing ligand docking studies and the ‘message-address’ concept. Multiple address sites were identified on the opioid receptors and structural modifications were proposed for the naltrexone derivatives for their enhanced selectivity. In the third project, structural modeling of the active state conformation of the κ-opioid receptor covalently bound to a salvinorin A derivative (agonist) was attempted via molecular dynamics simulations. Although the obtained molecular model lacked the signature ‘agonist-like’ conformations, the result provides a template for such studies in the future.
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Goldberger, Natalie Elizabeth. "A comprehensive investigation into the molecular mechanism responsible for selective androgen receptor (SARM) tissue-selectivity". Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1202342545.
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Livesey, Matthew Robert. "Molecular determinants of single channel conductance and ion selectivity in cationic Cys-loop receptor channels". Thesis, University of Dundee, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510623.
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Facey, Glenn Angus Carleton University Dissertation Chemistry. "Solid state NMR studies of the chiral selectivity, molecular motion and reactivity of guest molecules in tri-o-thymotide clathrates". Ottawa, 1991.
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Malmberg, Michelle. "Probing the G protein selectivity of FR900359 by means of molecular modeling and site directed mutagenesis". Thesis, Umeå universitet, Farmakologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-132256.
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Abrams, Christopher John. "Studies of the molecular basis of selectivity and gating in the inward rectifier potassium channel Kir2.1". Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29921.
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1. The molecular basis of selectivity and gating were investigated in wild-type and mutant forms of the inward rectifier K+ channel Kir2.1 (IRK1). 2. Kir2.1 channels show characteristic time-dependent gating kinetics due to a reversible voltage-dependent channel block by cytoplasmic polyamines. Mutations at Asp 172 in the M2 domain revealed that a negative charge at this position is the main criterion of time-dependent gating kinetics in Kir2.1. 3. Kir channels are blocked by Cs+ and Rb+ in a voltage-dependent manner, characteristic of many Kir channels. Rb+ and Cs+ block in Kir2.1 was abolished by replacing Asp 172 by Asn, but was re-established by a change to Gln, narrowing the pore. However, blocking affinity was reduced by the mutation to Gln. 4. When Asp 172 was mutated to Glu, narrowing the pore but retaining the negative charge, block by both Cs+ and Rb+ was increased relative to wild-type. 5. Replacing Gly 168 in M2 by Ala was suggested to widen the pore at position 172. The effect of this mutation on Cs+ and Rb+ block was relatively small. 6. There appears to be a balance between charge and pore size in determining whether icons block or permeate. A major part of the selectivity of Kir2.1 is associated with Asp 172 in the M2 domain. This site also determines the time-dependent activation gating of the channel. 7. Mutation of Asp 172 to Ser were predicted to abolish both Cs+ and Rb+ block in Kir2.1, but blocking affinity was similar to WT. Therefore, other properties of the pore must contribute to Cs+ and Rb+ block at position 172 in addition to the electrostatic and steric effects identified in this study.
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Giovanola, M. "MOLECULAR INSIGHTS IN ION ACCESS, DEPENDENCE AND SELECTIVITY IN THE NSS/SLC6 TRANSPORTERS KAAT1 AND GAT1". Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/232725.
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In this thesis we have investigated some aspects of the molecular physiology of the amino acid transporter KAAT1 and of the GABA transporter GAT1 both belonging to the Neurotransmitter:Sodium Symporter (NSS) family. Wild type as well mutants of these proteins were investigated after expression in Xenopus laevis oocytes and functionally analyzed by radiochemical and electrophysiological assays.
In the first chapter a general overview of the biological importance of membrane proteins is provided jointly to a description of the Xenopus oocytes as expression system for this kind of proteins. The second part of the chapter is presenting the general physiological features of KAAT1 and GAT1 while the last part collects information regarding the thermodynamic aspects of secondary active transport as well as the characteristics of the bacterial amino acid transporter LeuT and of the insect dopamine transporter DAT, the two structural models of the NSS family. The last part of the chapter presents one of the most intriguing and cutting edge aspects in the field of membrane transporters: the role of symmetry in the process of ferrying substrates through the lipid bilayer.
In chapter 2 are reported the results of our investigation of a highly conserved glycine triplet in KAAT1; this sequence is conserved at the Extracellular Loop 1 (EL1) in almost all the members of the NSS family but the data available at the beginning of our research for GAT1 and for the serotonin transporter SERT were not exhaustive and not in full agreement one to each other. We found that in KAAT1 the flexibility that these amino acids provide to the EL1 is of fundamental importance for the cation access to the extracellular vestibule of the protein. The role that we propose could justify the high degree of conservation showed by this stretch of residues in order to allow the driver ion to get access to its binding site.
Different aspects of KAAT1 molecular physiology are addressed in the chapter 3. With our experiments we were able to link the potassium selectivity that characterizes KAAT1 to the polarity of Na1 site and to the dimensional flexibility that is provided in Na2 site by a KAAT1 specific residue of glycine. Beside cation selectivity, we explored the weak chloride dependence of KAAT1 providing new evidences of the fact that its interaction with chloride occurs in an almost unique fashion. The analysis of the 3D homology model of KAAT1 allowed us to identify Thr67 as a residue that we proved experimentally to be a key molecular hinge for the coupling mechanism of ion and substrate flux realized by KAAT1. Furthermore this residue is involved in the initial stereochemical selection that the transporter operates on its substrates as well in the chloride dependence of the transport mechanism.
Chapter 4 will briefly resume some preliminary data concerning the possibility to combine the insect Sf9 cell line from Spodoptera frugiperda with the highly efficient Baculovirus expression system with the aim of obtaining the adequate amount of purified protein for KAAT1 crystallization.
The last chapter gathers the results of our analysis regarding the influence of internal chloride in the reverse operational mode of the GABA transporter GAT1. Our results provides a link between the oscillations of the intracellular concentration of this anion with the calcium independent GABA release that is described in different pathological and physiological conditions.
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Alexander, Leila Tamara. "Mutational analysis of isoform selectivity and conformational equilibria in protein kinase inhibition". Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:6a2a12f6-4787-4398-81c0-fa5d6afe96f0.
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Deregulation of protein kinases is associated with many diseases making them important targets for therapeutic intervention. Kinases can switch between active and inactive conformations that can be targeted by type 1 or type 2 inhibitors respectively. One of the most relevant conformational switches is the ‘in’ and ‘out’ movement of the ATP/Mg2+ binding motif DFG. Factors modulating the conformational equilibria such as the residue environment of regulatory motifs remain poorly understood despite their importance for drug discovery. In this thesis, the first model system tested the hypothesis that accessibility of the DFG-out conformation is restricted by the energetic cost of transition between the in and out states. CDK2 was chosen as a target that was thought to have an inaccessible DFG-out conformation, and several point mutations were introduced to promote this conformational transition. Detailed biochemical and biophysical characterisation illustrated that the mutants bound type 2 inhibitors more potently than the wild type. In addition, the wild-type CDK2 was shown to bind type 2 inhibitors in the absence, but not in the presence, of cyclin. The first known CDK2 co-crystal structure in the DFG-out conformation was solved, opening the door to a new class of CDK2 inhibitors. In the second project, site-directed mutagenesis was used to explore the residues determining inhibitor selectivity between PIM1 and PIM2. Evaluation of ligand binding to the variants and comparison of PIM1 and PIM2 crystal structures showed that flexibility of the phosphate-binding loop was the dominant factor determining the differences in their affinities for ATP and small molecule inhibitors. These studies illustrate that residues contributing to kinase conformational equilibria can be just as important for inhibitor binding as contact residues formed in the ligand complex.
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Stankovic, Ivana 1986. "Dinâmica molecular de celulases : estudos de reconhecimento de substrato e propriedades conformacionais". [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/248865.
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Orientador: Munir Salomão SkafTese (doutorado) - Universidade Estadual de Campinas, Instituto de Química
Made available in DSpace on 2018-08-25T12:12:30Z (GMT). No. of bitstreams: 1 Stankovic_Ivana_D.pdf: 27307159 bytes, checksum: 42c2cb1272b20efd40baf8597dd8f156 (MD5) Previous issue date: 2014
Resumo: A degradação enzimática da celulose proveniente de biomassa para a produção de bioetanol é realizada por um conjunto de proteínas denominadas celulases, as quais são produzidas por vários fungos e bactérias. O mecanismo molecular das interações físicas entre as celulases e a celulose é pouco conhecido. Para investigar estas interações, bem como as propriedades conformacionais e dinâmicas, nesta Tese usamos simulações por dinâmica molecular (MD). Abordamos duas celulases: a Endoglucanase 3 de Trichoderma harzianum (ThEG3) e a Endoglucanase de Xanthomas campestris pv. campestris (XccEG). O estudo dos mecanismos de reconhecimento de substrato por ThEG3 que falta o módulo de ligação à celulose (CBM), revela que a ausência de um CBM nesta estrutura é compensada pela presença de resíduos similares aos resíduos típicos de um CBM. O segundo estudo, sobre seletividade da XccEG, explica por que esta enzima catalisa a hidrólise somente de oligossacarídeos de cadeia igual ou maior que quatro unidades. Nossas simulações indicam que os quatro subsítios característicos da fenda de ligação ao substrato da XccEG precisam ser simultaneamente estabilizados pelas interações com substrato para promover uma ligação efetiva substrato-enzima. No terceiro estudo, investigamos as propriedades mecânicas do linker entre o domínio catalítico (CCD) e o CBM desta mesma enzima, composto por blocos de Thr e Pro, utilizando a técnica de replica exchange MD. Nossos resultados sugerem as bases moleculares da maior rigidez deste linker em comparação ao linker de celobiohidrolases II de Trichoderma reesei. Por fim, adaptamos o método de MDFF (flexible fitting MD) para gerar modelos de estrutura terciária a partir de dados de SAXS e o aplicamos para criar um modelo da estrutura intacta CCD-linker-CBM de XccEG
Abstract: The enzymatic degradation of the cellulose for the production of bioethanol is performed by a group of proteins called cellulases which are produced by various fungi and bacteria. The molecular mechanism of the physical interactions between the cellulases and a cellulose is little-known. In this work we use molecular dynamics simulations (MD) to investigate these interactions as well as conformational and dynamic properties. We have studied two cellulases: the endoglucanase 3 from Trichoderma harzianum (ThEG3) and the endoglucanase from Xanthomas campestris pv. campestris (XccEG). The study of the mechanisms of substrate recognition by ThEG3 which lacks the cellulose binding module (CBM) shows that the absence of a CBM in this structure is compensated by the presence of residues similar to typical CBM residues. The second study, on the selectivity of XccEG, explains why this enzyme catalyses only the hydrolysis of four or more units long oligosaccharides. Our simulations indicate that the four characteristic subsites of the substrate binding cleft of XccEG need to be simultaneously stabilized by the interactions with the substrate to provide an effective enzyme-substrate binding. In the third study, we investigated the mechanical properties of the linker between the catalytic domain (CCD) and CBM of the same enzyme, composed of Thr-Pro blocks, using the replica exchange molecular dynamics (REMD). Our results suggest the molecular basis of greater rigidity of this linker in comparison to the linker of cellobiohydrolase 2 from Trichoderma reesei. Finally, we have adapted the method of Molecular Dynamics Flexible Fitting (MDFF) to generate tertiary structure models from SAXS data and applied it to create a model of the intact structure CCD-linker-CBM of the XccEG
Doutorado
Físico-Química
Doutora em Ciências
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Bakir, Ilyas. "Molecular studies of the γ-secretase complex activity and selectivity towards the two substrates APP and Notch". Thesis, Mälardalen University, School of Sustainable Development of Society and Technology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-9622.
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Alzheimer Disease (AD) is the most common neurodegenerative disorder in the world. One of the neuropathological hallmarks of AD is the senile plaques in the brain. The plaques are mainly composed of the amyloid β (Aβ) peptide. Aβ is generated from the amyloid precursor protein, APP, when it is first cleaved by the β-secretase and subsequently the γ-secretase complex. The γ-secretase complex cleaves at different sites, called γ and ε, where the γ-cleavage site generates Aβ peptides of different lengths and ε-cleavage generates the APP intracellular domain (AICD). The two major forms of Aβ is 40 and 42 amino acids long peptides, where the latter is more prone to aggregate and is the main component in senile plaques. The γ-secretase complex is composed of four proteins; Pen-2, Aph-1, nicastrin and presenilin (PS). The PS protein harbours the catalytic site of the complex, where two aspartate residues in position 257 and 385 (Presenilin 1 numbering) are situated. Most Familial AD (FAD) mutations in the PS gene cause a change in the γ-cleavage site, leading to a shift from producing Aβ40 to the longer more toxic variant Aβ42. Frequently, this often leads to impairments of the AICD production. Another substrate for the γ-secretase complex is Notch. It is important to maintain the Notch signaling since an intracellular domain (NICD) is formed after cleavage by the γ-secretase complex in the membrane (S3-site) and this domain is involved in transcription of genes important for cell fate decisions.
It has been reported that certain APP luminal juxtamembrane mutations could drastically alter Aβ secretion, however their effect on AICD production remains unknown. In this study we want to analyse wether the juxtamembrane region is important for the AICD production. To gain more insight into the luminal juxtamembrane function for γ-secretase-dependent proteolysis, we have made a juxtamembrane chimeric construct. A four-residue sequence preceding the transmembrane domain (TMD) of APP (GSNK), was replaced by its topological counterpart from the human Notch1 receptor (PPAQ). The resulting chimeric vector C99GVP-PPAQ and the wildtype counterpart were expressed in cells lacking PS1 and PS2 (BD8) together with PS1wt. We observed that the chimeric construct did not alter production of AICD when using a cell based luciferase reporter gene assay monitoring AICD production. We also introduced a PS1 variant lacking a big portion of the large hydrophilic loop, PS1∆exon10, since our group has previously observed that this region affect Aβ production143. We found that the absence of the large hydrophilic loop in PS1 gave a 2-fold decrease in AICD-GVP formation from C99GVPwt compared to PS1wt. The activity of PS1wt and PS1Δexon10 using C99GVP-PPAQ as a substrate gave similar result as the C99GVPwt substrate, i.e. a 2-fold decrease in AICD-GVP formation when comparing PS1Δexon10 with PS1wt. From this data we therefore suggest that the four residues in the juxtramembrane domain (JMD) (GSNK) is not altering ε-cleavage of APP when changed to Notch1 counterpart, PPAQ. Furthermore, we also show that the 2-fold decrease in AICD-production by the PS1Δexon10 molecule is not changed between the two substrates C99GVPwt and C99GVP-PPAQ. This indicates that the luminal region of APP is not directly involved in the ε-site processing. If the luminal region is affecting processing in the γ-cleavage sites, remains however to be investigated.
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Cimenler, Ummuhan. "Molecular-Size Selective Zeolite Membrane Encapsulated Novel Catalysts for Enhanced Biomass to Liquid (BTL) Processes". Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6644.
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80% of energy usage in the word comes from fossil fuels (coal, oil, natural gas) and among the fossil fuels, oil is the most consumed energy source especially in transportation. However, due to concerns about energy demand and energy sustainability, global warming and dependency on foreign oil, generation of renewable fuels is crucial for transportation. Biomass to Liquid (BTL) is a promising process available to produce renewable liquid fuels. BTL fuels have great potential to meet the growing demand for liquid fuels, mitigating climate change, and providing value to rural areas. However, there are two major challenges with biofuels produced from BTL. One of the major challenge is the H2:CO ratio of biomass gasification product is insufficient for production of hydrocarbon fuels due to formation of methane and tars. The steam reforming of hydrocarbons, to improve the H2:CO ratio, is generally conducted as part of the gas conditioning. However, tars cause the catalysts to deactivate rapidly. Secondly, for fuels produced from the gasification route regardless of feedstock source, there is an economy-of-scale issue. Therefore, it is desirable to seek ways of process intensification to allow small scale plants to be more economical. Zeolites can be used to solve these challenges since they have reactant selectivity property.
To achieve a catalyst capable of reforming methane without potential for deactivation by tars, the encapsulation of a core reforming catalyst with porous zeolite shell is examined in this dissertation. After detailed introduction in the first chapter, a composite H-β zeolite membrane encapsulated 1.6wt%Ni/1.2wt%Mg/Ce0.6Zr0.4O2 steam reforming catalyst was prepared by a physical coating method in the second chapter of the study. Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (EDS) analyses indicated that H-β zeolite was coated successfully on the core reforming catalyst. The pore size of H-β zeolite shell was between 0.43 and 0.57 nm, as measured by the HK method. Steam reforming of CH4 and C7H8 (as a tar model) were conducted with the composite H-β zeolite coated reforming catalyst, the two components individually, and physical mixtures of the two components as a function of temperature (780–840°C). CH4 conversion was enhanced by a factor of 2–3 (depending on temperature) for the composite catalyst as compared to the core reforming catalyst individually even though the zeolite did not have any activity alone. Possible reasons for the enhanced CH4 conversion include confined reaction effects (increase residence time within pores) of the catalyst containing the zeolite coating and/or Al3+ promotion of the active sites. Alternatively, due to molecular-size selectivity, the composite H-β zeolite coated reforming catalyst demonstrated a decrease in C7H8 conversion when compared to the uncoated reforming catalyst. The results validate the use of size selective catalysts to control molecular traffic and enhance the reforming reactant selectivity.
A composite catalyst consisting of an outer layer of zeolite membrane encapsulating an inner reforming catalyst core was synthesized by a double physical coating method to investigate reactant selectivity (ratio of methane/toluene conversion rate) in steam reforming of methane (CH4) and toluene (C7H8). A double encapsulation (51 wt % H-β zeolite) of a 1.6 wt % Ni−1.2 wt % Mg/Ce0.6Zr0.4O2 steam reforming catalyst was compared to a singly coated composite catalyst (34.3 wt % H-β zeolite) to investigate zeolite thickness effects on the conversion of different sized hydrocarbons. The increase in the zeolite content from 34.3 to 51 wt % decreased both CH4 and C7H8 conversions (by up to 14% depending upon the temperature) as a result of the increase in diffusional limitations. Weisz−Prater criteria and Thiele moduli calculations confirmed that the reactions were performed under internal diffusion limitations. The C7H8 conversion of the 51 wt % composite (SR@β51%) catalyst was similar to the zeolite alone, indicating negligible contribution from the protected catalyst core. The reactant selectivity increased by up to 1.5 times on SR@β51% in comparison to the SR@β34.3% composite. Combined reforming at 800 °C on the SR@β51% catalyst indicated that the catalyst was stable during the 10 h time on stream.
Continuing this work, a non-acidic Silicalite-1 zeolite membrane encapsulated 1.6wt%Ni-1.2wt%Mg/Ce0.6Zr0.4O2 steam reforming composite catalyst, synthesized by a physical coating method, was used to investigate effect of encapsulation on size selective steam reforming, using methane (CH4) and toluene (C7H8) as representative species. Weisz-Prater Criteria and Thiele moduli calculations indicated internal diffusion limitations. Combined reforming of CH4 and C7H8 at 800°C on the composite catalyst demonstrated stability during the 10 h time on stream while uncoated SR catalyst deactivated. The non-acidic Silicalite-1 encapsulated catalyst showed decreases (~2-7%) in both CH4 and C7H8 conversions compared to acidic H-β zeolite confirming that shell acidity did contribute to conversion and suggesting that shell defects/grain boundaries were responsible for the C7H8 conversion.
Finally, low temperature 0.16wt%Pt–1.34wt%Ni–1.00wt%Mg/(Ce0.6Zr0.4)O2 reforming catalyst was triple coated with H-β zeolite (60 wt% of zeolite) to be utilized synthesis of combination steam reforming catalyst (SR) and Fischer-Tropsch Synthesis (FTS) catalyst (CRAFT) for a single-step conversion of methane to liquid fuels. Scanning electron microscopy (SEM) image and energy-dispersive spectroscopy (EDS) analysis result demonstrated that H-β zeolite was successfully encapsulated onto the low temperature reforming catalyst. The catalyst was tested in steam reforming of methane (CH4) and toluene (C7H8) and the results was compared with 51 wt%. While CH4 conversions are very similar on the 60wt% composite catalyst with 51wt% composite catalyst, no C7H8 conversion was seen on the 60 wt% composite catalyst. Thus, it is concluded that the 60 wt% composite catalyst can be utilized to synthesis CRAFT catalyst.
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Medda, Federico. "Novel cambinol analogues as potential anticancer agents : an improved understanding of sirtuin isoform selectivity". Thesis, University of St Andrews, 2011. http://hdl.handle.net/10023/1839.
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SIRT1 and SIRT2 are two NAD⁺-dependent deacetylases which negatively modulate the activity of p53, a protein which is involved in cell cycle arrest, senescence and apoptosis following genotoxic stress. Part I of the thesis describes the exploration of the chemical space around a reported unselective and modest inhibitor of SIRT1 and SIRT2 with the aim of improving the selectivity and potency of the inhibitor against the two isoforms. Particular emphasis is placed upon understanding the mode of binding of the novel analogues within the active site of the enzymes. Chapter 1 reviews the physiological roles of class III NAD⁺-dependent deacetylases, also known as sirtuins. In particular, the application of SIRT1 and SIRT2 inhibitors as potential anticancer agents is described. Amongst these, only cambinol and the tenovins showed in vivo activity in a mouse xenograft model. Previously only one analogue of cambinol had been reported in the literature. Chapter 2 describes the development of a small collection of novel cambinol analogues (First Generation Studies). The role played by different substituents at the phenyl group and at the N-1 of the thiouracil core is discussed. Along with the synthesis and structure activity relationship (SAR) associated with the core structure, in-cell experiments intended to confirm the activity of the most active compounds are reported. Chapter 3 provides a rationalisation for the SAR discussed in Chapter 2. Based on computational molecular modelling studies (GOLD), the activity of the most potent and selective SIRT2 inhibitors is explained. Two series of novel cambinol analogues were designed (Second and Third Generation Analogues) in order to assess further the proposed binding mode. Chapter 4 focuses on the development of the “Second Generation” analogues, characterised by the presence of lipophilic substituents at the sulfur atom and at the N-3 position of the thiouracil core. The synthesis, biological evaluation and SAR are discussed in detail. Chapter 5 reports the development of the “Third Generation” analogues, characterised by either a benzyl group or para-alkoxy-substituted benzyl group at the N-1 position of cambinol. Once again, the synthesis, biological evaluation and SAR data are presented. An improved understanding of the mode of binding of the novel compounds is proposed based on molecular dynamics (MD) studies. Indole-based alkaloids, such as Vincristine and Vinblastine, are well known for their anticancer activity. Recently, the anticancer activity of members of the calycanthaceous family of alkaloids has been discovered. Part II of the thesis focuses on model studies aimed at developing the total synthesis of one of these compounds, perophoramidine. Chapter 7 provides an overview of the calycanthaceous alkaloid family of natural products, including their biological properties. The structural features of perophoramidine, along with the previously reported synthetic studies are outlined. Chapter 8 describes the synthesis of an advanced intermediate in the total synthesis of dehaloperophoramidine, a structural analogue of perophoramidine Problems encountered, optimisation studies and the synthesis of a re-designed intermediate are also reported in this chapter.
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Ketcha, Wanda Germain Jean Magloire. "Characterisation of oestrogenic properties of Isoflavones derived from Millettia griffoniana Baill.: - Molecular mode of action and tissue selectivity". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1154000965292-60098.
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Six isoflavones derived from Millettia griffoniana namely, 4’-methoxy-7-O-[(E)-3-methyl-7hydroxymethyl-2,6 octadienyl]isoflavone (7-O-DHF), Griffonianone C (Griff C), 7-O-geranylformononetin (7-O-GF), 3’,4’-dihydroxy-7-O-[(E)-3,7-dimethyl-2,6-octadienyl]isoflavone (7-O-GISO), Griffonianone E (Griff E), 4’-O-geranylisoliquiritigenin (4-O-GIQ) were tested for potential oestrogenic activities in three different oestrogen receptor alpha (ERα) dependent assays, namely a recombinant yeast assay, a reporter gene assay based on stably transfected MCF-7 cells (MVLN cells) and the induction of alkaline phosphatase in Ishikawa cells. The oestrogenic activities of isoflavones from Millettia griffoniana could be completely suppressed by the pure oestrogen antagonist, fulvestrant. The expression of Ki-67, proliferating cell nuclear antigen (PCNA) and cyclin D1 (CD1) mRNA used as indicator of cell proliferation in MCF-7 cells was assayed. Based on these in vitro results, Griff C was further tested in vivo. The main objective of this part of the work was to study the mechanistic basis of the oestrogenicity Three different doses of Griff C (2, 10, or 20 mg/kg BW) of Griff C in ovariectomised Wistar rats. 17β-oestradiol (E2: 10 µg/kg BW) was used as positive control. They were treated daily for three consecutive days and sacrificed 24 hours after receiving the last dose. The whole uterus was removed and weight. Liver and vena cava fragments were also collected and stored together with uteri in liquid nitrogen for subsequent real-time PCR to evaluate the effects of Griff C on the regulation of some relevant oestrogen–responsive genes in the uterus, the liver and the vena cava. The role of Griff C in apoptosis or in cell survival, through mediation of the phosphatidylinositol 3 kinase-Akt (PI3K-Akt) signaling pathway, was also investigated. Western blot analysis revealed that Griff C slightly increased the phosphorylation of Akt at its serine 473 residue. In this work, oestrogenic properties of the isoflavones derived from Millettia griffoniana are described using reporter gene assays and the oestrogen-inducible alkaline phosphatase Ishikawa model for the first time. These in vitro data were verified in vivo showing the regulation of the expression of various relevant oestrogen-responsive genes by Griff C. The spectrum of its activity was clearly similar to that of 17β-oestradiol on uterine hepatic and vena cava tissues of ovariectomised rats except for the proliferative response. However Griff C remained 100 to 1000 times less effective than oestradiol. These findings confirmed that some of the biological effects attributed to Millettia griffoniana are closely related to oestrogen-mediated action.
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Nita, Sorin. "Insights into the solvation and selectivity of chiral stationary phases using molecular dynamics simulations and chemical force microscopy". Thesis, Kingston, Ont. : [s.n.], 2008. http://hdl.handle.net/1974/1348.
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Brandt, Bjoern. "Selectivity in hydrocarbon conversions and methanol decomposition on a Pd/Fe 3 O 4 model catalyst". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2008. http://dx.doi.org/10.18452/15854.
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Selektivität zu erreichen ist eines der Hauptziele der Chemie. In der Katalyse wird allgemein von einem engen Zusammenhang zwischen der Selektivität und der Katalysatorstruktur ausgegangen - allerdings erschwert die komplexe mikroskopische Struktur realer Katalysatoren ein tiefergehendes Verständnis; daher wird versucht, weitergehende Erkenntnisse an strukturell vereinfachten Materialien zu gewinnen. Für diese Arbeit wurde hierzu ein Pd/Fe3O4-Modellkatalysator verwendet. Auf diesem System wurde die Selektivität in zwei katalytische Modellreaktionen untersucht. Die Reaktantenexposition erfolgte dabei über Molekularstrahlen im Hochvakuum, und die Reaktionsraten wurden massenspektrometrisch gemessen; Adsorbate wurden IR-spektroskopisch detektiert. - Zersetzung von Methanol: Es wird gezeigt, dass Methanol auf dem Oxid Fe3O4 sehr selektiv durch Reaktion mit Oberflächensauerstoff (Mars-van-Krevelen-Mechanismus) zu Formaldehyd und Wasser dehydrogeniert wird. Auf Pd-Metall zersetzt sich Methanol im wesentlichen sehr schnell zu Kohlenstoffmonoxid und Wasserstoff (bzw. zu Kohlenstoffablagerungen in einer Nebenreaktion). Es werden Experimente gezeigt, die darauf hindeuten, dass Diffusion von oxidgebundenem Methanol/Methoxy auf die Pd-Metallpartikel signifikant zur Gesamtaktivität des Modellkatalysators beiträgt. - Umsetzung von 2-Buten mit Deuterium: Zunächst wird gezeigt, dass die Erzielung katalytischer Aktivität kritisch von der dissoziativen Adsorption des Reaktanden Deuterium abhängt, die durch Kohlenwasserstoffadsorbate stark inhibiert wird; es war allerdings möglich, diese Limitierung experimentell zu umgehen. Darüberhinaus wird gezeigt, dass die Hydrierungsreaktion durch die Anwesenheit stark zersetzter Kohlenwasserstoffablagerungen selektiv induziert werden kann, während die alternative Reaktion (H/D-Austausch/Isomerisierung) auch in Abwesenheit dieser Spezies abläuft; mögliche Erklärungsmodelle werden diskutiert. Schließlich wird die mögliche Ursache für die unter bestimmten Reaktionsbedingungen beobachteten unterschiedlichen Reaktionsraten mit cis- und trans-2-Buten als Reaktanten diskutiert.The achievement of selectivity is one of the main objectives in chemistry. For catalysis, selectivity is generally seen to be closely linked with catalyst structure; the complex microscopic structure of real catalysts, however, obstructs to obtain a deeper understanding; for this reason, structurally simplified materials are studied. For the current work, studies have been conducted on a Pd/Fe3O4 model catayst. On this system, the selectivity in two catalytic reactions has been examined. The exposure of the reactants was effected by molecular beams in high vacuum, and the reaction rates have been measured mass spectrometrically; additionally, adsorbates were detected by IR-spectroscopy. - Decomposition of Methanol: It is shown that on the oxide Fe3O4 methanol is dehydrogenated very selectively to formaldehyde and water by reaction with surface oxygen of the oxide (Mars-van-Krevelen mechanism). On Pd metal it is mainly decomposed very quickly to carbon monoxide and hydrogen (and, in a side reaction, to carbonaceous deposits). Experiments are shown indicating that the diffusion of oxide-related methanol and methoxy to the Pd metal-particles contributes significantly to the overall activity of the model catalyst. - Conversion of 2-Butene with Deuterium: At first it is shown that the catalytic activity depends critically on the dissociative adsorption of the reactant deuterium, which is strongly inhibited by hydrocarbon adsorbates; it was, however, possible to overcome this limitation experimentally. In addition, it is shown that the hydrogenation reaction can be selectively induced in the presence of strongly dehydrogenated carbonaceous deposits, whereas the alternative reaction (H/D-exchange/isomerisation) can proceed also without the presence of those species; possible models for explanation are discussed. Finally, the possible origin of the different reaction rates with cis- and trans-2-butene that were observed only under certain reaction conditions is discussed.
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Werner, Martin. "Low-Scaling Local and Fragment Self-Consistent Field Potentials in Molecular Systems". Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2017. http://hdl.handle.net/11858/00-1735-0000-002E-E311-5.
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Ayaz, Muhammad [Verfasser], Ralf [Akademischer Betreuer] Kaldenhoff e Gerhard [Akademischer Betreuer] Thiel. "Investigations on mercury sensitivity and molecular determinants of selectivity in two plant aquaporins. / Muhammad Ayaz. Betreuer: Ralf Kaldenhoff ; Gerhard Thiel". Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2011. http://d-nb.info/1105564169/34.
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Sun, Shangzheng. "Building up molecular complexity by Ni-catalyzed cross-coupling reactions". Doctoral thesis, Universitat Rovira i Virgili, 2020. http://hdl.handle.net/10803/670603.
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En línia amb la investigació desenvolupada al nostre grup basada en l’elaboració de noves reaccions d’acoblament
creuat, hem decidit centrar la tesis doctoral en l’estudi de la formació de nous enllaços Csp3–Csp3, utilitzant reaccions
d’acoblament creuat reductores catalitzades per níquel.
Al primer capítol, els nostres esforços es centren en la preparació d’una nova metodologia basada en l’alquilació
reductiva de a-haloboronats, utilitzant com a matèria prima olefines no activades. Aquest nou protocol, quimio- i
regioselectiu, permet l’incorporació d’un fragment alquílic-boronat a olefines no activades, mitjançant condicions de
reacció suaus. Per altra banda, l’ús d’olefines internes permet la formació d’enllaços carboni-carboni en posicions C–H
sp3 llunyanes, a través del procés anomenat “chain-walking” catalitzat per níquel. Al segon capítol, continuant amb el
nostre interès en reaccions catalitzades per níquel, hem estudiat un mètode catalític d’alquilació desaminativa
d’olefines no activades. Aquesta nova metodologia opera sota condicions de reacció suaus i es caracteritza per l’ampli
espectre de compostos que poden acoblar-se selectivament. Aquesta tècnica pot tenir aplicació en el context de la
derivatització de l’etilè i per la funcionalització de molècules d’alt valor afegit.En línea con la investigación desarrollada en nuestro grupo basada en la elaboración de reacciones de acoplamiento cruzado, hemos decidido centrar la tesis doctoral en el estudio de la formación de enlaces Csp3–Csp3, usando reacciones de acoplamiento cruzado reductoras catalizadas por níquel. En el primer capitulo, nuestros esfuerzos se centran en la preparación de una nueva metodología basada en la alquilación reductiva de a-haloboronatos usando como materia prima olefinas no activadas. Este protocolo, quimio- y regioselectivo, permite la incorporación de un fragmento alquílico-boronato en olefinas no activadas, y presenta unas condiciones de reacción suaves. Por otro lado, el uso de olefinas internas permite la formación de enlaces carbonocarbono en posiciones C-H sp3 lejanas, a través del proceso llamado “chain-walking”, catalizado por níquel. En el segundo capitulo, siguiendo nuestro interés en reacciones catalizadas por níquel, hemos estudiado un método catalítico de alquilación desaminativa de olefinas no activadas. Esta nueva metodología opera bajo condiciones de reacción suaves y se caracteriza por el amplio espectro de compuestos que pueden acoplarse selectivamente. Esta técnica también puede ser aplicada en el contexto de la derivatización del etileno y para la funcionalización de moléculas de alto valor añadido.
In line with our group research interests on cross-coupling-reactions, we decided to focus this doctoral studies on the development of sp3 C–C bond formation by means of nickel catalyzed reductive-cross-coupling. Our first effort was focused on the development of a reductive alkylation of a-haloboronates with unactivated olefin feedstocks. We have developed a mild, chemo- and site-selective catalytic protocol that allows the incorporation of an alkylboron fragment into unactivated olefins. Moreover, the use of internal olefins enables C C bond-formation at remote sp3 C-H sites via nickel catalyzed chain-walking process. Following up our interest on nickel catalyzed chainwalking events, we reported a site-selective catalytic deaminative alkylation of unactivated olefins. This method operates under mild conditions and is characterized by a wide substrate scope and exquisite site-selectivity profile. Particularly noteworthy is that this technique could be employed in the context of ethylene derivatization and for the late-stage functionalization of complex molecules. Our final efforts for the sp3 C–C bond formation was focused on the development of a regio-selective cross-coupling of three electrophiles by means of nickel/photoredox dual catalysis. We developed a modular, chemo- and regio-selective 1,2-difunctionalization of simple vinyl boronates with readily available organic halides.
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Rungta, Meha. "Carbon molecular sieve dense film membranes for ethylene/ethane separations". Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/50121.
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The current work focused on defining the material science options to fabricate novel, high performing ethylene/ethane (C₂H₄/C₂H₆) separation carbon molecular sieve (CMS) dense film membranes. Three polymer precursors: Matrimid®, 6FDA-DAM and 6FDA:BPDA-DAM were used as precursors to the CMS membranes. CMS performances were tailored by way of tuning pyrolysis conditions such as the pyrolysis temperature, heating rate, pyrolysis atmosphere etc. The CMS dense film membranes showed attractive C₂H₄/C₂H₆ separation performance far exceeding the polymeric membrane performances. Semi-quantitative diffusion size pore distributions were constructed by studying the transport performance of a range of different penetrant gases as molecular sized probes of the CMS pore structure. This, in conjunction with separation performance data, provided critical insights into the structure-performance relationships of the CMS materials. The effects of testing conditions, i.e. the testing temperature, pressure and feed composition on C₂H₄/C₂H₆ separation performance of CMS dense films were also analyzed. These studies were useful not just in predicting the membrane behavior from a practical stand-point, but also in a fundamental understanding of the nature of CMS membrane separation. The study helped clarify why CMS membranes outperform polymeric membrane performance, as well as allowed comparison between CMS derived from different precursors and processing conditions. The effects on C₂H₄/C₂H₆ separation in the presence of binary gas mixture were also assessed to get a more realistic measure of the CMS performance resulting from competition and bulk flow effects. The current work thus establishes a framework for guiding research ultimately aimed at providing a convenient, potentially scalable hollow fiber membrane formation technology for C₂H₄/C₂H₆ separation
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Gomes, Marcelo do Nascimento. "Planejamento, síntese guiada por QSAR, avaliação biológica e modelagem molecular de chalconas com atividade antituberculose". Universidade Federal de Goiás, 2017. http://repositorio.bc.ufg.br/tede/handle/tede/7372.
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Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG
In view of the current panorama of tuberculosis (TB) pandemic in the world, aggravated by co-infection with the HIV virus and the emergence of resistant strains of Mycobacterium tuberculosis (M. tb.), The research and discovery of new Anti-TB drugs. The present work aimed at the planning, synthesis and biological evaluation of new compounds with anti-TB activity, candidates for TB drugs. Structure and activity relationship (SAR) studies were developed using Matched Pair Molecular Analysis (MMPA) and binary models of quantitative relations between structure and activity (QSAR) using a combination of molecular fingerprints and machine learning methods. Bioisosteric replacement were proposed to plan new aryl and heteroaryl chalcones using the information obtained from SAR and QSAR analyses. Thirty-three compounds were selected by the consensus QSAR model for the synthesis. These compounds were synthesized and their structures confirmed by infrared (IR), hydrogen nuclear magnetic resonance (1H NMR) and carbon (13C NMR) spectroscopic methods and mass spectrometry (MS). Compounds which showed high purity (≥95% in HPLC) were tested against strains of M. tb. H37Rv (sensitive) and resistant to rifampicin (RMP) or isoniazid (INH). In addition, they were also tested in mammalian cell cytotoxicity assays and activity spectrum. We identified 22 hits with anti-TB activity, with minimum inhibitory concentration (MIC) in M. tb. H37Rv in aerobic conditions (MABA) <10 μM. Of these, 12 compounds exhibited potent M. tb. replication activity on nanomolar scale, with MIC values in MABA <1 μM and in micromolar under anaerobic conditions (LORA) with MIC <10 μM. In addition, these compounds also showed potent inhibitory activity against monoresistant strains at RMP or INH (MIC <1 μM and MIC <10 μM, respectively). Hits also demonstrated low cytotoxicity in mammalian cells (Vero cells) and selectivity index between 11 and 545 for M. tb. The same selectivity was verified in the activity spectrum assay against four commensal strains and six strains of non-tuberculosis mycobacteria (NTMs), in which the compounds presented broad spectrum against the NTMs strains. These results demonstrated that the combination of in silico strategies for the design of aryl and heteroaryl chalcones was efficient in identifying new compounds that proved to be potent, selective and promising candidates for prototypes of anti-TB drugs.
Face ao panorama atual da pandemia de tuberculose (TB) no mundo, agravado pela co-infecção com o vírus HIV e o surgimento de cepas de Mycobacterium tuberculosis (M. tb.) resistentes aos fármacos utilizados, é urgente a pesquisa e descoberta de novos fármacos anti-TB. O presente trabalho objetivou o planejamento, a síntese e avaliação biológica de novos compostos com atividade anti-TB, candidatos a fármacos para TB. Foram desenvolvidos estudos de relação entre estrutura e atividade (SAR) utilizando o método Matched Pair Molecular Analysis (MMPA) e modelos binários de relações quantitativas entre estrutura e atividade (QSAR) utilizando combinação de descritores (fingerprints) moleculares e métodos de aprendizado de máquina. Substituições bioisostéricas foram propostas para planejar novas aril e heteroaril chalconas utilizando as informações obtidas nas análises de SAR e QSAR. Trinta e três compostos foram selecionados pelo modelo de QSAR por consenso para a síntese. Estes compostos foram sintetizados e suas estruturas foram confirmadas por métodos espectroscópicos no infravermelho (IV), de ressonância magnética nuclear de hidrogênio (RMN de 1H) e de carbono (RMN de 13C) e espectrometria de massas (EM). Os compostos que apresentaram elevado grau de pureza (≥95% em CLAE) foram testados contra cepas de M. tb. H37Rv (sensíveis) e resistentes a rifampicina (RMP) ou isoniazida (INH). Além disso, também foram testados em ensaios de citotoxicidade em células de mamíferos e espectro de atividade. Foram identificados 22 hits com atividade anti-TB, com concentração inibitória mínima (MIC) em M. tb. H37Rv em ensaios em condições aeróbias (MABA) <10 μM. Destes, 12 compostos exibiram potente atividade na replicação de M. tb em escala nanomolar, com valores de MIC em MABA <1 μM e em micromolar em condições anaeróbias (LORA) com MIC <10 μM. Ademais, esses compostos também apresentaram potente atividade inibitória contra cepas monoresitentes a RMP ou INH (MIC<1 μM e MIC<10 μM, respectivamente). Os hits também demonstraram baixa citotoxicidade em células de mamífero (células Vero) e índice de seletividade entre 11 e 545 para M. tb. A mesma seletividade foi verificada no ensaio de espectro de atividade frente a quatro cepas comensais e seis cepas de micobactérias não-tuberculose (NTMs), em que os compostos apresentaram amplo espectro contra as cepas NTMs. Estes resultados demonstraram que a combinação das estratégias in silico para o planejamento de aril e heteroaril chalconas foi eficiente na identificação de novos compostos que se mostraram potentes, seletivos e promissores candidatos a protótipos de fármacos anti-TB.
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Hamnevik, Emil. "Characterization and Directed Evolution of an Alcohol Dehydrogenase : A Study Towards Understanding of Three Central Aspects of Substrate Selectivity". Doctoral thesis, Uppsala universitet, Biokemi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-318984.
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Many different chemicals are used in the everyday life, like detergents and pharmaceuticals. However, their production has a big impact on health and environment as much of the raw materials are not renewable and the standard ways of production in many cases includes toxic and environmentally hazardous components. As the population and as the life standard increases all over the planet, the demand for different important chemicals, like pharmaceuticals, will increase. A way to handle this is to apply the concept of Green chemistry, where biocatalysis, in the form of enzymes, is a very good alternative. Enzymes do not normally function in industrial processes and needs modifications through protein engineering to cope in such conditions. To be able to efficiently improve an enzyme, there is a need to understand the mechanism and characteristics of that enzyme. Acyloins (α-hydroxy ketones) are important building blocks in the synthesis of pharmaceuticals. In this thesis, the enzyme alcohol dehydrogenase A (ADH-A) from Rhodococcus ruber has been in focus, as it has been shown to display a wide substrate scope, also accepting aryl-substituted alcohols. The aim has been to study the usefulness of ADH-A as a biocatalyst towards production of acyloins and its activity with aryl-substituted vicinal diols and to study substrate-, regio-, and enantioselectivity of this enzyme. This thesis is based on four different papers where the focus of the first has been to biochemically characterize ADH-A and determine its mechanism, kinetics and its substrate-, regio-, and enantioselectivity. The second and third paper aims towards deeper understanding of some aspects of selectivity of ADH-A. Non-productive binding and its importance for enantioselectivity is studied in the second paper by evolving ADH-A towards increased activity with the least favored enantiomer through protein engineering. In the third paper, regioselectivity is in focus, where an evolved variant displaying reversed regioselectivity is studied. In the fourth and last paper ADH-A is studied towards the possibility to increase its activity towards aryl-substituted vicinal diols, with R-1-phenyl ethane-1,2-diol as the model substrate, and the possibility to link ADH-A with an epoxide hydrolase to produce acyloins from racemic epoxides.
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Hernández, Prat Anna 1984. "Antitumor effects of novel targeted therapies (TAK-228 and TAK-117) with high selectivity againts PI3K/AKT/mTOR pathway in bladder cancer : Defining molecular markers". Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/664507.
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El càncer de bufeta avançat s'associa amb un mal pronòstic i amb opcions limitades de tractament. Tot i l’èxit recent amb l'ús d'inhibidors immunitaris, no tots els pacients responen a la teràpia i encara hi ha la necessitat d'opcions alternatives. La ruta de PI3K/AKT/mTOR està sobreactivada sovint en aquesta patologia i pot ser un objectiu terapèutic potencial per a la intervenció terapèutica. Es va estudiar l'eficàcia antitumoral del TAK-228, un inhibidor oral de mTORC1 / 2 en models preclínics de càncer de bufeta amb alteracions en la transducció de senyals d'aquesta via. Es va demostrar una forta inhibició de la proliferació cel·lular in vitro, i la reducció del creixement del tumor in vivo. Es van analitzar possibles biomarcadors de resposta. Es van observar forts efectes sinèrgics amb la combinació de TAK-228 i TAK-117 (inhibidor de PI3Kα). El TAK-228 va mostrar una millor eficàcia quan es va combinar amb el paclitaxel. Es necessitaran estudis addicionals amb el TAK-228 per veure si aquesta eficàcia terapèutica preclínica es tradueix en benefici clínic per a pacients amb càncer de bufeta.Advanced bladder cancer is associated with a poor prognosis and with limited treatment options. Despite of the recent success with the use of immune check-point inhibitors, not all patients will respond to therapy and there is still need for alternative options. PI3K/AKT/mTOR pathway is frequently activated in this pathology and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of TAK-228, an oral mTORC1/2 inhibitor in preclinical models of bladder cancer with signal transduction alterations of this pathway. We demonstrated strong inhibition of cell proliferation in vitro, and reduction of the tumor growth in vivo. Potential biomarkers of response are analysed. Strong synergistic effects were observed with the combination of TAK-228 and TAK-117 (PI3Kα inhibitor). TAK-228 did show improved efficacy when combined with paclitaxel. Further studies with TAK-228 will be needed to see if this preclinical therapeutic efficacy is translated into clinical benefit for selected bladder cancer patients.
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Szczepaniak, Florence. "Efficient sampling of complex biomolecular assemblies using molecular simulations". Electronic Thesis or Diss., Université de Lorraine, 2024. http://www.theses.fr/2024LORR0115.
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Les informations au niveau atomique sont essentielles pour décrire la structure et la dynamique des complexes biomoléculaires. Les travaux présentés dans cette thèse visent à explorer et à améliorer les techniques informatiques expliquant la formation de complexes, quantifiant les énergies libres de liaison ou décrivant la dynamique de systèmes multi-composants. J'ai d'abord développé un protocole pour calculer l'énergie libre de liaison d'un complexe protéine-ligand. Il s'appuie sur des transformations alchimiques réalisées dans un cadre mécanique statistique rigoureux. Le protocole est distribué au sein du plugin BFEE2, un outil conçu pour aider l'utilisateur à préparer tous les fichiers d'entrée nécessaires et à effectuer le post-traitement des simulations d'estimation d'affinité de liaison. La dynamique moléculaire (MD) et les simulations alchimiques ont été utilisées pour fournir des informations sur la formation de complexes protéiques spécifiques en termes de structure et de dynamique. L'ensemble des protéines Dpr et DIP, qui jouent un rôle clé dans la neuromorphogenèse du système nerveux de Drosophila melanogaster, offre un paradigme riche pour en apprendre davantage sur la reconnaissance protéine-protéine. De nombreux membres de la sous-famille DIP réagissent de manière croisée avec plusieurs membres de la famille Dpr et vice-versa. Bien qu'il existe un total de 231 hétérodimères Dpr-DIP possibles, seules 57 paires « apparentées » ont été détectées par des expériences de résonance plasmonique de surface (SPR), ce qui suggère que les 174 paires restantes ont une affinité de liaison faible ou peu fiable. Ici, j'ai évalué les performances des approches informatiques pour quantifier les affinités de liaison entre les protéines Dpr et DIP et j'ai identifié, au moyen d'une série de mutations ponctuelles, les résidus interfaciaux régissant la spécificité du processus de reconnaissance. En m'appuyant sur les transformations alchimiques, j'ai développé une méthode de simulation hybride dynamique moléculaire hors équilibre - Monte Carlo (neMD/MC) visant à améliorer l'échantillonnage de membranes inhomogènes, en contournant la lente diffusion latérale des différents constituants. Des molécules lipidiques choisies aléatoirement sont échangées pour générer des configurations qui sont ensuite acceptées ou rejetées selon un critère Metropolis basé sur le travail alchimique associé à la tentative d'échange calculé via une trajectoire courte. Les performances de l'algorithme hybride neMD/MC et sa capacité à échantillonner la distribution des lipides à proximité d'une hélice transmembranaire portant une charge nette sont illustrées pour un mélange binaire de lipides chargés et zwitterioniques. Pour maintenir l'équilibre entre un système simulé et un bain environnant infini, une version modifiée de l'algorithme neMD/MC a été développée, dans laquelle un lipide choisi au hasard dans le système simulé est échangée avec un lipide prélevé dans un système séparé faisant office de système thermodynamique. « réservoir » avec la fraction molaire souhaitée pour tous les composants lipidiques. En parallèle de ces simulations, la dynamique des canaux ioniques pentamères ligand-dépendants (pLGIC) est étudiée. Lors de la liaison avec un agoniste, la conformation des protéines change pour contrôler le transport des ions vers et hors des cellules. À l'aide de diverses structures liées à des récepteurs nicotiniques, des simulations MD sont calculées. La conductivité et la stabilité du pore des pLGICs à l'état désensibilisé sont mesurées. Il a également été démontré que les fonctions de ces protéines dépendent de la composition lipidique. En recourant à des simulations alchimiques, la différence d'affinité protéine-lipide est calculée avec des lipides anioniques et zwitterioniques liés à la protéineAtomic-level information is essential to describe the structure and dynamics of biomolecular assemblies. The work presented in this thesis aims to explore and enhance computational techniques explaining the formation of complexes, quantifying binding free energies or describing the dynamics of multi-components systems. I first developed a protocol to compute the binding free energy of a ligand buried in a membrane protein. It relies on alchemical transformations carried out in a rigorous statistical mechanical framework. The protocol is distributed within the BFEE2 plugin, a tool designed to assist the end user in preparing all the necessary input files and performing the post-treatment of the simulations towards the final estimate of the binding affinity. Molecular Dynamics (MD) and alchemical simulations have been employed to provide insights into the formation of specific protein complexes in terms of structure and dynamics. The set of Dpr and DIP proteins, which play a key role in the neuromorphogenesis in the nervous system of Drosophila melanogaster, offer a rich paradigm to learn about protein-protein recognition. Many members of the DIP subfamily cross-react with several members of the Dpr family and vice-versa. While there exists a total of 231 possible Dpr-DIP heterodimer, only 57 “cognate” pairs have been detected by surface plasmon resonance (SPR) experiments, suggesting that the remaining 174 pairs have low or unreliable binding affinity. Here I assessed the performance of computational approaches to in quantifying the binding affinities between Dpr and DIP proteins and I identified by means of a series of point mutations, the interfacial residues governing the specificity of the recognition process. Building on alchemical transformations, I developed a hybrid nonequilibrium molecular dynamics - Monte Carlo (neMD/MC) simulation method aimed at enhancing the sampling of inhomogeneous membranes, circumventing the slow lateral diffusion of the various constituents. Randomly chosen lipid molecules are swapped to generate configurations that are subsequently accepted or rejected according to a Metropolis criterion based on the alchemical work associated to the attempted swap calculated via a short trajectory. The performance of the hybrid neMD/MC algorithm and its ability to sample the distribution of lipids near a transmembrane helix carrying a net charge are illustrated for a binary mixture of charged and zwitterionic lipids. To enforce equilibrium between a simulated system and an infinite surrounding bath, a modified version of the neMD/MC algorithm was developed, in which a randomly chosen lipid molecule in the simulated system is swapped with a lipid picked in a separate system standing as a thermodynamic “reservoir” with the desired mole fraction for all lipid components. Membrane proteins function has been shown to depend on the lipid organization within the membrane either through averaged bulk effect or specific binding. A well-known class of protein exhibiting such a dependance is the family of pentameric ligand-gated ion channels (pLGICs). Upon the binding of a neurostransmitter, the conformation of these proteins changes establing a ionic current at the synapse junctions, transforming therby a chemical into an electric signal. Here, we generated several MD trajectories of various agonist-bound structures of nicotonic acethlycholine receptors solved by cryoEM, providing a molecular basis shedding light on the desensitization process. The conductivity and the stability of the pore of the pLGICs in a desensitized state are measured. The functions of these proteins have also been shown to depend on lipid composition. Finally, we employed alchemical tranformations to quantify the relative binding affinities of anionic and zwitterionic lipids at putative pLGIC binding sites, enlightening how lipids modulate the fonction of these proteins
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Zhang, Wei. "Directed Evolution of Glutathione Transferases with Altered Substrate Selectivity Profiles : A Laboratory Evolution Study Shedding Light on the Multidimensional Nature of Epistasis". Doctoral thesis, Uppsala universitet, Biokemi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-158400.
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Directed evolution is generally regarded as a useful approach in protein engineering. By subjecting members of a mutant library to the power of Darwinian evolution, desired protein properties are obtained. Numerous reports have appeared in the literature showing the success of tailoring proteins for various applications by this method. Is it a one-way track that protein practitioners can only learn from nature to enable more efficient protein engineering? A structure-and-mechanism-based approach, supplemented with the use of reduced amino acid alphabets, was proposed as a general means for semi-rational enzyme engineering. Using human GST A2-2*E, the most active human enzyme in the bioactivation of azathioprine, as a parental enzyme to test this approach, a L107G/L108D/F222H triple-point mutant of GST A2-2*E (thereafter designated as GDH) was discovered with 70-fold increased activity, approaching the upper limit of specific activity of the GST scaffold. The approach was further experimentally verified to be more successful than intuitively choosing active-site residues in proximity to the bound substrate for the improvement of enzyme performance. By constructing all intermediates along all putative mutational paths leading from GST A2-2*E to mutant GDH and assaying them with nine alternative substrates, the fitness landscapes were found to be “rugged” in differential fashions in substrate-activity space. The multidimensional fitness landscapes stemming from functional promiscuity can lead to alternative outcomes with enzymes optimized for other features than the selectable markers that were relevant at the origin of the evolutionary process. The results in this thesis suggest that in this manner an evolutionary response to changing environmental conditions can readily be mounted. In summary, the thesis demonstrates the attractive features of the structure-and-mechanism-based semi-rational directed evolution approach for optimizing enzyme performance. Moreover, the results gained from the studies show that laboratory evolution may refine our understanding of evolutionary process in nature.
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Stallivieri, Aurélie. "Synthèse de systèmes à base de photosensibilisateurs pour l'amélioration de la sélectivité tumorale en thérapie photodynamique". Thesis, Université de Lorraine, 2015. http://www.theses.fr/2015LORR0128/document.
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Une des limitations de la thérapie photodynamique est la faible sélectivité des photosensibilisateurs (PS) pour les tissus tumoraux. La recherche de nouveaux PS plus sélectifs s’est orientée vers la synthèse de PS couplés à des motifs afins pour des récepteurs membranaires surexprimés dans certains cancers. Le récepteur à l’acide folique est surexprimé dans les carcinomes ovariens et des PS ont été conjugués à de l’acide folique. Des PS ont aussi été couplés à un peptide spécifique de neuropiline 1 surexprimé au niveau des cellules tumorales de médulloblastome. Une autre stratégie pour augmenter la sélectivité du traitement vise à produire les espèces réactives de l’oxygène spécifiquement au niveau du site tumoral. L’activité de clivage enzymatique de marqueurs biologiques surexprimés dans les zones tumorales est utilisée. Les gélatinases (MMP-2 et -9) et leur activateur MMP-14 sont connues pour jouer un rôle primordial dans l'angiogenèse tumorale et la croissance du glioblastome multiforme. Différents photodynamic molecular beacons (PMB), associant un PS et un quencher lié par un peptide substrat des gélatinases et MMP-14, ont été développésOne limitation of photodynamic therapy is the low selectivity of photosensitizers (PS) to tumour tissue. The search of new PS more selective began to focus on the synthesis of PS coupled with substrate specific of the membrane receptors overexpressed in certain cancers. The acid folic receptor is overexpressed in ovarian carcinomas and PS were conjugated with folic acid. PS were also coupled with a specific peptide of neuropilin 1 overexpressed in tumoral cells of medulloblastoma. Another strategy for increasing the selectivity of the treatment is to produce reactive oxygen species specifically at the tumor site. The activity of enzymatic cleavage of biomarkers overexpressed in tumour areas is used. The gelatinases (MMP-2 and MMP-9) and their activator MMP-14 are known to play a key role in tumour angiogenesis and the growth of glioblastoma multiform. Different photodynamic molecular beacons (PMB), composed of a photosensitizer and a quencher linked together by a peptide substrate of gelatinases or MMP-14, were designed
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Cisek, Katryna. "Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis". The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338325484.
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Gonciaruk, Aleksandra. "Graphene and triptycene based porous materials for adsorption applications". Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/graphene-and-triptycene-based-porous-materials-for-adsorption-applications(932755b9-1600-4f64-8683-00844645a58b).html.
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There were three main driving forces behind this thesis: global concern over climate change mainly due to uncontrolled carbon dioxide (CO2) emissions, the excitement over the discovery of graphene and its versatile potential, and the potential to design three-dimensional (3D) or two-dimensional (2D) structures, in our case using unique triptycene molecule. We examined two polymeric materials for CO2 adsorption and suggested simple design of disordered carbons suitable for gas adsorption studies. The approach in each task was to examine structural and adsorption properties of materials using detailed atomistic modelling employing Monte Carlo and Molecular Dynamics techniques and where possible provide experimental measurements to validate the simulations. The thesis is presented as a collection of papers and the work can be divided into three independent projects. The aim of the first project is to utilize graphene as an additive in polymer composites in order to increase separation between the polymer chains increasing available surface area. The matrix used is a polymer of intrinsic microporosity (PIM-1), which possess large surface area and narrow nano-sized ( > 2nm) pore distribution attractive for gas separation membrane applications. Adding a filler can reduce aging of the polymer, and enhance permeability across the membrane, often to the expense of loosing selectivity. Therefore, we investigated the packing of PIM-1 chains in presence of discrete 2D graphene platelets and 3D graphene-derived structures and its effect on composite structure and adsorption properties. We found that additives do not alter structural polymer properties at the molecular level preserving the same adsorption capacity and affinity. Potential permeability increase would benefit from the retention of selectivity in the material. Building on design philosophy of materials with intrinsic microporosity we continued further investigation of 3D graphene-derived structures. The idea is that highly concave molecules or polymer chains pack inefficiently creating microporous materials with sufficient surface area for gas adsorption. 3D propeller-like structures were derived from graphene arms connected through the rigid triptycene and other types of cores. The resulting structures created a large amount of micropores and showed similar CO2/CH4 selectivity to activated carbons reported in the literature. It was shown that rigid triptycene core leads to more open structures. The model was also applied to model commercially available activated carbon to predict n- perfluorohexane adsorption. The fitting to experimental structural information proved to be challenging due to trial and error nature of the approach. Nevertheless, the simple packing procedure and diverse structure design have a great potential to serve as a virtual model for porous carbons that possess pore complexity and does not require any previous experimental data to be build on. The last project concerns CO2 adsorption and selectivity over CH4 and N2 in recently reported triptycene-based polymer. The triptycene shape polymer can form a porous 2D network that can be exfoliated into free-standing sheets and potentially used as a membrane. Sheets stack in the bulk material forming anisotropic channel pores. Additionally it contains fluoro- functional groups, which are known to have a high CO2 affinity. We explored pore structure and chemistry of stacked material for gas adsorption and predicted comparable capacity and CO2 selectivity to other microporous covalent materials such as activated carbons and PIMs. The CH4/N2 selectivity was similar to currently most selective material belonging to MOF family. We showed that fluoro-group have a positive effect on CO2 affinity, however predictions are sensitive to the charges of fluorine atoms assigned by different methods.
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Cabana, Jérôme. "Étude des déterminants structuraux de l'activation des voies de signalisation de la protéine G[indice inférieur q/11] et des β-arrestines par le récepteur de type 1 à l'angiotensine II". Thèse, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/7706.
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Résumé : La signalisation biaisée représente la capacité des récepteurs couplés aux protéines G (RCPG) d'engager des voies de signalisation distinctes avec des efficacités variables selon le ligand utilisé ou la mutation dans le récepteur. Un meilleur contrôle des voies activées ou inhibées par des médicaments pourrait permettre de réduire leurs effets indésirables. Malheureusement, les mécanismes structuraux impliqués dans la transmission du signal à travers la membrane plasmique par l'entremise des RCPG sont peu connus, ce qui limite le développement rationnel de nouvelles molécules ciblant des voies de signalisation particulières. Le récepteur de type 1 à l'angiotensine II (AT[indice inférieur 1]), un RCPG de classe A prototypique, peut activer différents effecteurs suite à sa stimulation par le ligand endogène angiotensine II (AngII), incluant la protéine G[indice inférieur q/11] et les β-arrestines. Il est suggéré que l'activation de ces deux voies de signalisation peut être associée à des conformations différentes du récepteur AT[indice inférieur 1]. Pour vérifier cette hypothèse, nous avons utilisé des simulations de dynamique moléculaire afin d'explorer les interactions et les mouvements qui définissent le paysage conformationnel du récepteur AT[indice inférieur 1]. De plus, nous avons vérifié comment était modifié le paysage conformationnel par des mutations (N111G, N111W et D74N) et des ligands (AngII et [Sar[indice supérieur 1], Ile[indice supérieur 8]]AngII) ayant des profils signalétiques différents pour la voie de la protéine G[indice inférieur q/11] et la voie des β-arrestines. Les résultats obtenus nous éclairent sur le rôle d'un réseau de ponts hydrogène entre des résidus polaires conservés au coeur du récepteur dont font partie les résidus N111[indice supérieur 3.35] et D74[indice supérieur 2.50]. Les résultats révèlent la présence d'un groupe de résidus hydrophobes juste au-dessus du réseau de ponts hydrogène et adjacent à la pochette de liaison du récepteur qui semble important pour la stabilisation de l'état inactif du récepteur ainsi que pour son activation par un ligand. Dans l'ensemble, les résultats suggèrent que l'activation de la voie de la protéine G[indice inférieur q/11] est associée avec une transition conformationnelle spécifique stabilisée par l'agoniste alors que l'activation de la voie des β-arrestines est associée à une stabilisation de l'état de repos du récepteur.Abstract: Biased signaling represents the ability of G protein-coupled receptors to engage distinct pathways with various efficacies depending on the ligand used or on mutations in the receptor. Having better control over the signaling pathways activated or inhibited by drugs could lead to fewer undesirable effects. Unfortunately, the structural mechanisms involved in the transmission of signal across the cell membrane through the receptors are poorly understood, which limits the rational development of new molecules targetting specific signaling pathways. The angiotensin-II type 1 (AT[subscript 1]) receptor, a prototypical class A G protein-coupled receptor, can activate various effectors upon stimulation with the endogenous ligand angiotensin-II (AngII), including the G[subscript q/11] protein and β-arrestins. It is believed that the activation of those two pathways can be associated with distinct conformations of the AT[subscript 1] receptor. To verify this hypothesis, microseconds of molecular dynamics simulations were computed to explore interactions and movements that define the conformational landscape of the AT[subscript 1] receptor. We have also verified how this conformational landscape is modified by mutations (N111G, N111W, D74N) and ligands (AngII, [Sar[superscript 1]Ile[superscript 8]]AngII) that have different signaling properties on the G[subscript q/11] pathway and the β-arrestin pathway. The results provide a better understanding of the role of a hydrogen bond network formed of conserved polar residues in the receptor core which include residues N111[superscript 3.35] and D74[superscript 2.50]. The results also reveal the existence of a cluster of hydrophobic residues located right above the hydrogen bonds network and adjacent to the binding pocket that appears important for the stabilization of the ground state of the receptor as well as its ligand-induced activation. As a whole, the results suggest that activation of the G[supbscript q/11] pathway is associated with a specific conformational transition stabilized by the agonist, whereas the activation of the β-arrestin pathway is linked to the stabilization of the ground state of the receptor.
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Patt, Antoine. "Simulation moléculaire d'hydrates de gaz mixtes en conditions astrophysiques". Thesis, Bourgogne Franche-Comté, 2020. http://www.theses.fr/2020UBFCK008.
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Dans ce travail de thèse, des méthodes de simulations numériques ont été utilisées pour modéliser à l'échelle moléculaire des clathrates hydrates, dans des conditions thermodynamiques typiques des milieux astrophysiques. L'objectif était de caractériser, à l'aide des outils habituels du milieu de l'adsorption, les capacités de piégeage de ces structures particulières de l'eau. Les résultats présentés dans ce mémoire se concentrent sur un couple d'espèces chimiques, abondantes dans notre environnement astrophysique et relativement similaires : le monoxyde de carbone, CO, et le diazote, N2. Ainsi, les clathrates purs de CO et de N2, et l'hydrate mixte CO-N2 ont été étudiés, principalement à l'aide de simulations Monte-Carlo, dans l'ensemble grand canonique. En premier lieu, ces clathrates ont été examinés en les considérant au sein de cristaux infinis. Une encapsulation préférentielle des molécules de CO par rapport à celles de N2 a pu être mise en évidence dans les simulations, en accord avec des données expérimentales récentes et des calculs thermodynamiques. En second lieu, les systèmes d'hydrates ont été mis en contact avec une interface gazeuse pour étudier l'adsorption de CO et N2 en surface. Des simulations avec d'autres formes d'eau solide, aussi présentes dans les milieux astrophysiques, ont été menées. Toutes les surfaces considérées se sont avérées être encore plus sélectives dans le piégeage des molécules de CO que les cages constituant les clathratesIn this PhD work, numerical simulation methods have been used in order to model clathrate hydrates at the molecular scale, in thermodynamic conditions typical of astrophysical contexts. The aim was to characterize the trapping abilities of those peculiar structures of water, by means of the tools used in adsorption studies. The results presented in the present thesis are focused on a couple of chemical species which are found to be abundant in our astrophysical vicinity and are quite similar: carbon monoxide, CO, and nitrogen, N2. Thus, the single-component clathrates of CO and N2, and the mixed hydrate CO-N2 have been studied, mainly using grand canonical Monte Carlo simulations. First, these clathrates have been examined as part of a bulk phase. A preferential encapsulation of CO molecules, with respect to N2 molecules, has been highlighted in the simulations, in agreement with recent experimental data and thermodynamic calculations. Secondly, the hydrate systems have been brought in contact with a gaseous interface in order to study the surface adsorption of CO and N2 molecules. Simulations with other forms of solid water, also found in astrophysical contexts, have been performed. All the considered surfaces have shown a greater molecular selectivity towards the trapping of CO molecules, compared to the one of hydrates' cages
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Ferrari, Florent. "Étude de la sélectivité d'acylation enzymatique de peptides : prédiction de la sélectivité de la lipase B de Candida antarctica par modélisation moléculaire et recherche de nouvelles enzymes spécifiques de type aminoacylases". Thesis, Université de Lorraine, 2014. http://www.theses.fr/2014LORR0252/document.
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Les peptides sont des molécules pouvant posséder une activité biologique intéressante (antibiotique, anti-oxydante, antivirale, anti-hypertensive…). Ce sont cependant des molécules difficiles à utiliser car elles possèdent un faible temps de demi-vie in vivo et sont peu bio-disponibles. Le greffage d’un acide gras permet de les protéger et d’accroître leur potentiel d’action. Cette réaction appelée acylation peut être catalysée par des enzymes. A l’heure actuelle, peu de recherches sont faites sur l’acylation de peptides par voie enzymatique et sur la recherche de nouveaux biocatalyseurs adaptés pour cette réaction. Les objectifs de cette thèse ont été, dans un premier temps, de comprendre les mécanismes de la sélectivité d’acylation de peptides de la lipase B de Candida antarctica par une approche de modélisation moléculaire combinant docking et dynamique moléculaire, couplée à une approche expérimentale. Cette étude a permis d’identifier des interactions enzyme-substrats impliquées dans la sélectivité enzymatique et a permis de construire un modèle expliquant la régio- et chimio-sélectivité de l’acylation peptidique catalysée par cette enzyme. Dans un deuxième temps, une étude préliminaire a été menée afin d’identifier de nouvelles enzymes de type acylases présentes dans des surnageants de culture de différentes espèces de Streptomyces. Ces enzymes sont capables de catalyser des réactions d’acylation de peptides en milieux aqueux. Une méthode de semi-purification a été établie et une étude comparative a été menée sur la sélectivité d’acylation de la lipase B de C. antarctica et celle de nouvelles enzymes de type aminoacylases présentes dans un extrait protéique de surnageant de culture de Streptomyces ambofaciens. Ces nouvelles enzymes présentent une spécificité différente de celle de la lipase B de C. antarctica, permettant notamment, une acylation des acides aminés sur leur fonction amine en position α. Une caractérisation partielle des activités amino-acylase du surnageant de culture de S. ambofaciens a été réalisée. Dans une troisième et dernière partie, une comparaison des séquences génétiques a été réalisée entre treptomyces mobaraensis et S. ambofaciens afin d’identifier les gènes codant pour les acylases découvertes chez S. ambofaciens. Des mutants de S. ambofaciens délétés pour ces gènes ont été construits et la fonctionnalité des enzymes codées par ces gènes a été vérifiée ; enfin, une expression hétérologue de l’ε-lysine acylase a été initiéePeptides exhibit various beneficial effects such as antioxidant, anti-hypertensive, neuroprotective, antiviral or antimicrobial activities. However, their use can be limited by their short half-life and their low biological availability. One solution to overcome these drawbacks is the acylation of peptides with fatty acids. This reaction called acylation can be catalyzed using enzymes. To date, very few studies focus on enzymatic acylation of peptides and on finding new enzymes catalyzing this reaction. The objectives of this work were, in a first time, to understand the selectivity mechanisms of the lipase B of Candida antarctica for peptides acylation combining experimental and molecular modeling approaches. This study highlighted enzyme/substrate interactions involved in the enzymatic selectivity and a modelexplaining the chemo- and regio-selectivity of this enzyme for peptide acylation reactions was built. In a second time, a preliminary study was carried out in order to identify new aminoacylase enzymes produced in the culture supernatant of various species of Streptomyces. These enzymes are able to catalyze acylation of peptides in aqueous media. A partial purification method was set and a comparative study was performed on the selectivity of C. antarctica lipase Band that of the new aminoacylases discovered in the culture supernatant of Streptomyces ambofaciens ATCC 23877. These enzymes presented a selectivity different from C. antarctica lipase B allowing the acylation of the N-terminal amino group of amino acids or peptides. A partial description of the aminoacylase activity of the supernatant crude extract of S. ambofaciens was performed. In a third and final part, a comparison of sequences of aminoacylases from Streptomyces mobaraensis with the genome of S.s ambofaciens ATCC 23877 was performed in order to identify genetic sequences encoding the new discovered aminoacylases from S. ambofaciens ATCC 23877. Each identified gene was deleted to correlate it with the aminoacylase activity observed in the crude extract of S. ambofaciens. Lastly, a heterologous expression of the ε-lysine acylase was initiated
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Spencer, William John. "Phorbol ester-mediated NF-kappa-B transactivation is selectively inhibited by taxol". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0007/MQ44286.pdf.
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Hijazi, Mohamad. "Capteur de gaz SnO2 fonctionnalisé fonctionnant à température ambiante, sensible et sélectif pour la détection d’ammoniac". Thesis, Lyon, 2017. http://www.theses.fr/2017LYSEM030/document.
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Dans le domaine de la santé, l’analyse de l'haleine expirée offre un outil simple et non invasif pour le diagnostic précoce des maladies. Les capteurs de gaz à base de SnO2 modifies semblent être des dispositifs prometteurs pour détecter les gaz polaires tels que l'ammoniac. Dans cette étude, la fonctionnalisation de la surface de SnO2 a été réalisée afin d'obtenir un capteur de gaz sensible et sélectif à l'ammoniac, qui fonctionne à température ambiante. La première étape de la fonctionnalisation est la fixation covalente d’un film de 3-aminopropyltrethoxysalane (APTES) sur SnO2 en phase vapeur ou liquide. Les caractérisations effectuées par Spectroscopie Infrarouge et Spectrométrie photoélectronique X montrent qu’une quantité plus importante d'APTES a été greffée en phase liquide hydratée. La deuxième étape consiste à fonctionnaliser le SnO2-APTES avec des molécules contenant du chlorure d'acyle avec différents groupes tel que des groupes alkyle, acide et ester. Les capteurs modifiés par des acides et des esters sont sensibles à l’ammoniac entre 0,2 et 10 ppm à température ambiante. Cependant, le SnO2 APTES modifié par l’ester s'est révélé être plus sélectif que le capteur modifié par l'acide pour l’ethanol et le mondxyde de carbone. Ces résultats impliquent que la réponse est générée par les groupes fonctionnels acide et ester, NH3 modifie le moment dipolaire de la couche moléculaire greffée, ce qui entraine une modification de la conductance de SnO2. Le fonctionnement à température ambiante est l'un des avantages de ces capteurs, tout comme leur sélectivité à l'ammoniac en regard d'autres gaz tels que l'éthanol, le monoxyde de carbone et l'acétoneOne of the major challenges in the modern era is how we can detect the disease when we are still feeling healthy via noninvasive methods. Exhaled breath analysis is offering a simple and noninvasive tool for early diagnosis of diseases. Molecularly modified SnO2 sensors seem to be promising devices for sensing polar gases such as ammonia. SnO2 surface functionalization was performed in order to obtain sensitive and selective ammonia gas sensor that operates at room temperature. The first step of functionalization is the covalently attachment of 3-aminopropyltriethoxysilane (APTES) film on SnO2 in vapor or liquid phases. The characterization performed by the Infrared Spectroscopy and X-ray Photoelectron Spectroscopy, show that more APTES were grafted by hydrous liquid phase silanization. The second step was the functionalization of APTES modified SnO2 with molecules having acyl chloride of end functional groups molecules such as alkyl, acid and ester groups. Pure SnO2 and APTES modified SnO2 sensors did not show any significant sensitivity to ammonia (0.2-100 ppm) at 25 °C. On the contrary, acid and ester modified sensors are sensitive to ammonia between 0.2 and 10 ppm at room temperature. However, ester modified SnO2 was more selective than acid modified sensor regarding the ethanol and carbon monoxide gases. Ammonia variates the attached molecular layer’s dipole moment which leads to change in SnO2 conductance. Working at ambient temperature is also one of the advantages of these sensors in addition to the selectivity to ammonia regarding other gases such as ethanol, carbon monoxide and acetone
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Dobrowolski, Curtis Noel. "HISTONE LYSINE METHYLTRANSFERASES SELECTIVELY RESTRICT HIV-1 IN CENTRAL MEMORY T-CELLS". Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1522842870401743.
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Elson-Schwab, Lev. "Selectivity in the interactions between positively charged small molecules and negatively charged biopolymers". Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3221498.
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Thesis (Ph. D.)--University of California, San Diego, 2006.Title from first page of PDF file (viewed June 27, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Pickup, Michael Brennan. "New methodology in the determination of sequence-selectivity in small molecule-DNA binding". Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286346.
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Sun, Xixi. "Scaffolding Catalysis: Towards Regioselective Hydroformylation of Alkenes and Site-Selective Functionalization of Polyhydroxylated Molecules". Thesis, Boston College, 2013. http://hdl.handle.net/2345/3324.
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Thesis advisor: Kian L. TanChapter 1. We reported the first synthesis of all-carbon quaternary centers via hydroformylations using a catalytic directing group. With the ability of reversibly and covalently binding to a substrate, and coordinating to a metal center, scaffolding catalyst 1.1 is able to direct the branch-selective hydroformylation of 1,1-disubstituted olefins under mild temperature. Chapter 2. We have designed and synthesized a chiral organocatalyst 2.11. This catalyst is able to covalently bind to one hydroxyl, and utilize the induced intramolecularity to stereoselectively functionalize the other hydroxyl within a cis-1,2-diol via electrophile transfer. Catalyst 2.11 was used in the desymmetrization of meso-1,2-diols under mild conditions (4 C to room temperature), leading to high yields and selectivities for a broad substrate scope. Chapter 3. Catalyst 3.1 and 3.6 were demonstrated to selectively bind to primary hydroxyls over secondary hydroxyls. By combining the binding selectivity with asymmetric catalysis, these scaffolding catalysts were shown to promote the selective silylation of secondary hydroxyls within terminal (S)-1,2-diols. The reversal of substrate bias was further applied to a regiodivergent kinetic resolution of racemic terminal 1,2-diols, producing secondary protected products in synthetically practical levels of enantioselectivity (>95:5 er) and yields (≥40%). Time course studies of this reaction further revealed the optimal condition to form the primary silylated product in high s-factor. Chapter 4. Based on the previous understanding of catalyst 4.5 and 4.6, the exclusive catalyst recognition of cis-1,2-diols within polyhydroxylated molecules was further discovered. This unique functional group display recognition was further allied with the catalyst's ability to stereoselectively differentiate hydroxyls within cis-1,2-diols, enabling the site-selective protection, functionalization, and activation of the inherently less reactive axial hydroxyl groups within carbohydrates. This methodology also enables the selective functionalization of multiple complex molecules, including digoxin, mupirocin, and ribonucleosides, demonstrating the potential power of scaffolding catalysis in the rapid access to valuable synthetic derivatives of polyhydroxylated compounds
Thesis (PhD) — Boston College, 2013
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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Leeson, Philip. "Computer modelling of calixerene compounds capable of selectively extracting lanthanide metals from nuclear waste slurries". Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484312.
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