Dissertations / Theses: 'Binding kinetics'

1

Talbert, Ann Marie. "Drug protein binding kinetics from chromatographic profiles." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406921.

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Fisher, Joshua. "In Vitro Binding Kinetics of ChemoFilter with Cisplatin." Thesis, University of California, San Francisco, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10165379.

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Introduction: Endovascular chemotherapy treatment allows localized delivery adjacent to the target tumor; allowing an increased dosage and decreased leakage to other areas. It also allows for the opportunity to filter chemotherapy escaping the target tumor and entering the bloodstream. The ChemoFilter - a temporarily deployable, endovascular device will do just that; reducing systemic toxicity thus reducing adverse side effects from chemotherapy treatment. This will allow further increased dosage, increased tumor suppression, and increased tolerance to treatment. ChemoFilter has successfully filtered the chemotherapeutic Doxorubicin, but had yet to be tested in other chemotherapeutics. This study evaluates binding with new chemotherapeutics: Cisplatin, Carboplatin, and a cocktail comprised of Cisplatin and Doxorubicin.

Materials and Methods: ChemoFilter prototypes based on: 1.) Genomic DNA and 2.) Dowex (ion-exchange) resin, were evaluated for their ability to bind chemotherapy in vitro in phosphate-buffered saline (PBS). ChemoFilter was tested free in solution and encapsulated in nylon or polyester mesh packets of various dimensions. Concentrations were quantified using inductively coupled plasma mass spectrometry (IPC-MS), ultraviolet-visible spectrophotometry (UV-Vis), or fluorospectrometry. ¹¹C, ¹³C, and/or ¹⁴C radiolabeling Carboplatin began for in vitro and in vivo ChemoFilter quantification. In vitro quantification can include scintillation and/or gamma counting. In vivo may include Positron Emission Tomography (PET) imaging, Hyperpolarized ¹³C Magnetic Resonance Imaging (MRI), and/or Magnetic Resonance Spectroscopy (MRS) for real-time visualization. Reactions were verified using High Performance Liquid Chromatography (HPLC) for chemical species identification.

Results and Discussion: Results indicate significant and nearly complete, ~99% (p<0.01) clearance of Cisplatin using the DNA ChemoFilter sequestered in Nylon mesh, quantified with gold standard ICP-MS (evidenced at 214 and 265 nm). The Ion-exchange ChemoFilter has significant clearance, within seconds, of both Doxorubicin and Cisplatin mixed in a cocktail solution. However, it appears some Cisplatin is binding to the Nylon Mesh itself. Size, shape, and material of the mesh have been optimized. A potential mechanism for ¹¹C, ¹³C, or ¹⁴C radiolabeling of Carboplatin has been developed and early results have been successful. ChemoFilter works much more efficiently when sequestered in nylon packets of specific geometries. Significant improvements have been made to ChemoFilter, moving the device closer to clinical trials.

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3

Goold, Richard David. "The glutathione S-transferases : kinetics, binding and inhibition." Doctoral thesis, University of Cape Town, 1989. http://hdl.handle.net/11427/27175.

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The glutathione S-transferases are a group of enzymes which catalyse the conjugation of reduced glutathione with a variety of electrophilic molecules, and they are therefore thought to play a major role in drug biotransformation and the detoxification of xenobiotics. The cytosolic GSH S-transferase isoenzymes of rat, man and mouse have been assigned to three groups, Alpha, Mu and Pi, based on N-terrninal amino acid sequences, substrate specificities, immunological cross-reactivity and sensitivities to inhibitors. The kinetic mechanism of the GSH S-transferases is controversial, due to the observation of non-Michaelian (non-hyperbolic) substrate-rate saturation curves. The most detailed investigations of the steady-state kinetics of glutathione S-transferase have been performed with isoenzyme 3-3 (class Mu) and the substrate 1,2-dichloro-4-nitrobenzene (DCNB). Explanations for the apparently anomalous non-hyperbolic kinetics have included subunit cooperativity, steady-state mechanisms of differing degrees of complexity and the superimposition of either product inhibition or enzyme memory on these mechanisms. This study has confirmed the biphasic kinetics for isoenzyme 3-3 with DCNB and shown non-hyperbolic kinetics for this isoenzyme with 1-chloro-2,4-dinitrobenzene (CDNB) and for isoenzyme 3-4 with DCNB and CDNB. It is proposed that the basic steady-state random sequential Bi Bi mechanism is the simplest mechanism sufficient to explain the non-hyperbolic kinetics of GSH S-transferases 3-3 and 3-4 under initial rate conditions. Neither more complex steady-state mechanisms nor the superimposition of product inhibition or enzyme memory on the simplest steady-state mechanism are necessary.

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Thumser, Alfred Ernst Adolf. "The glutathione S-transferases : inhibition, activation, binding and kinetics." Thesis, University of Cape Town, 1990. http://hdl.handle.net/11427/28958.

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Shiffler, Stacy Marla. "Binding Kinetics of FlAsH and AsCy3 to Tetra-Cysteine Peptides." Thesis, The University of Arizona, 2011. http://hdl.handle.net/10150/144943.

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6

Willumsen, Bodil. "Kinetics of biological binding studied by flow injection fluorescence microscopy /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/8519.

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7

Zhang, Fang. "The regulation of conformation and binding kinetics of integrin alphaLbeta2." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/24678.

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Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2008.
Committee Chair: Zhu, Cheng; Committee Member: Babensee , Julia; Committee Member: Garcia, Andres; Committee Member: McIntire, Larry; Committee Member: Selvaraj, Periasamy; Committee Member: Springer, Timothy

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8

Kasturi, Rama. "Kinetics of calmodulin binding to its smooth muscle target proteins /." The Ohio State University, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487694702782747.

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9

Chernoff, Daniel Michael. "Kinetics of local anesthetic binding to sodium channels : role of pKaÌ³." Thesis, Massachusetts Institute of Technology, 1988. http://hdl.handle.net/1721.1/29203.

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Thesis (Ph. D.)--Harvard University--Massachusetts Institute of Technology Division of Health Sciences and Technology, Program in Medical Engineering and Medical Physics, 1989.
On t.p. "a" is subscript.
Includes bibliographical references (leaves 165-175).
by Daniel Michael Chernoff.
Ph.D.

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Lee, Isaish Chi Kin. "Measuring the binding kinetics of estrogen receptor alpha and dietary estrogens." HKBU Institutional Repository, 2014. https://repository.hkbu.edu.hk/etd_oa/28.

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Anti-estrogen drugs such as Tamoxifen and Raloxifene are widely prescribed for breast cancer patients. While they are effective, they also have serious side effects. Alternative drugs are therefore being developed. In the drug discovery process, the in vitro binding of estrogen receptors and lead compounds were studied. The binding strength was conventionally quantified in terms of equilibrium dissociation constants (K0 ). However, the binding kinetic rates and especially off-rates (k0 ff) were recently shown to be better indicators of drug potency. In this thesis, we identified a few dietary estrogens as candidate lead compounds. We studied the binding of full-length human recombinant ERa with these dietary estrogens. In particular, we measured for the first time their binding kinetics rate constants. We also measured the change in the receptor-ligand binding kinetics upon its recruitment of co-activators, as a means to gauge agonist/antagonist propensity ofthe ligand. Our results showed that the following dietary estrogens, a-Zearalenol, Zearalenone, and Coumestrol bind favorably to the estrogen receptor alpha.

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Donovan, Benjamin Thomas. "Nucleosome Regulation of Transcription Factor Binding Kinetics: Implications for Gene Expression." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1574774626880568.

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Neumann, Brittany M. "Mechanism of PTEN binding to model membranes." Digital WPI, 2018. https://digitalcommons.wpi.edu/etd-dissertations/176.

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PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a potent tumor suppressor. PTENâ€™s tumor suppressor action is rooted in its phosphatase function on the lipid substrate phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P3). PTENâ€™s enzymatic activity is specific for the third position of the inositol headgroup. PI(3,4,5)P3 is a second messenger that is a part of the PI3K-Akt pathway, and its dysregulation leads to constitutively activated AKT. The result of AKT activation is cell cycle progression, motility, cell growth, and proliferation, and consequently, overaction leads to neoplastic growth and tumorigenesis. PTEN antagonizes this pathway by regulating PI(3,4,5)P3 population through its phosphatase activity which produces the lipid PI(4,5)P2 (phosphatidylinositol-(4,5)-bisphosphate). A result of PTENâ€™s function is that its activity must be localized at the PM (plasma membrane) since this is where its substrate resides. Additionally, the mole percent of the phosphoinositide family of lipids is small. From highest percent composition to lowest the phosphoinositide species in the PM rank as PI(4,5)P2 (~2%), PI(4)P (~1%), and PI(3,4,5)P3 (~0.02%). For PTEN to turn over its substrate, it must first translocate from the cytosol to the PM and then search through the plasma membrane for this rare but high in demand lipid. This is at the center of the scarcity paradox. This work explores how PTEN may overcome this paradox by using its multiple lipid binding domains to interact with multiple lipid partners to efficiently localize it toward a region with a high probability of having PI(3,4,5)P3. This hypothesis is tested using two kinetic methodologies. First, we use pre- steady state stopped-flow spectrometry to determine the rates that govern PTEN-lipid binding. Second, we use single-molecule total internal reflectance fluorescence (smTIRF) microscopy to resolve the diffusion coefficients and dwell times of bound PTEN on SLBs supported lipid bilayers (SLBs). We test PTEN against various lipid compositions to determine how the bilayer structure in addition to the chemistry of the lipid influences the enzymeâ€™s binding. These compositions include PI(4,5)P2, PI phosphatidylinositol (PI), phosphatidylserine (PS), PI(4,5)P2/PI and PI(4,5)P2/PS. In addition to this kinetic work, we will also present a novel model membrane platform that takes advantage of a microfluidic device to develop lateral lipid gradients in SLBs. This microfluidic platform, in the future, will allow for the investigation of the dynamic behavior of proteins interacting with lipids but with a bilayer that has a structure recapitulating polarized membranes like in chemotaxing cells.

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Ganotra, Gaurav Kumar [Verfasser], and Rebecca [Akademischer Betreuer] Wade. "Computational studies of drug-binding kinetics / Gaurav Kumar Ganotra ; Betreuer: Rebecca Wade." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/122050646X/34.

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Ganotra, Gaurav K. [Verfasser], and Rebecca [Akademischer Betreuer] Wade. "Computational studies of drug-binding kinetics / Gaurav Kumar Ganotra ; Betreuer: Rebecca Wade." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/122050646X/34.

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Alcantara, Edwin P. "Electrophysiology, receptor binding kinetics, and mutational analysis of Bacillus thuringiensis S-endotoxin /." The Ohio State University, 1997. http://rave.ohiolink.edu/etdc/view?acc_num=osu148794790840198.

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16

Pettersson, John. "Single Molecule Studies of hGSTA1-1: Binding Kinetics and Active Site Dynamics." Research Showcase @ CMU, 2015. http://repository.cmu.edu/dissertations/620.

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The human detoxification enzyme glutathione s-transferase alpha 1 (GSTA1-1) is known for its ability to conjugate a variety of different hydrophobic xenobiotics to the tripeptide glutathione. The conjugation can be catalyzed through either a substitution or an addition reaction. Which reaction mechanism is being used affects the cooperativity of the enzyme. GST is also capable of catalyzing isomerization reactions of particular substrates without conjugation to GSH which further extends its repertoire. The C-terminal of the enzyme transitions from a random loop to an α-helix that localizes over the active site as a ligand binds. The α-helix is also involved in product release. We hypothesize that the broad substrate specificity and the catalytic flexibility of GST is a result of a heterogeneous protein population where multiple conformers with different properties coexist. To identify different conformers in a population a single molecule approach is needed. Fluorescently tagged substrates and products of GSTA1-1 have been imaged as they bind immobilized GSTA1-1 using TIRF microscopy. Single molecule binding events can be analyzed to characterize different binding states of the enzyme. The observation of at least two average occupancy times suggests that there are multiple binding states and conformations of the enzyme. One of these binding states is dominating the population and a large number of binding events has to be sampled to pick up the more rare states. To further characterize the behavior of GSTA1-1 FRET and DEER have been used to study the active site dynamics during binding of a ligand. Unlike X-ray crystallography, DEER and FRET provide a distribution in a distance between groups, and not just an average. Our data suggest that binding of S-hexylglutathione does not localize the C-terminal helix which is contrary to what can be observed in the X-ray crystal structure. Glutathione alone is sufficient to localize the helix. This highlights the importance of using proteins in solution to study their conformation.

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Ganotra, Gaurav K. [Verfasser], and Rebecca C. [Akademischer Betreuer] Wade. "Computational studies of drug-binding kinetics / Gaurav Kumar Ganotra ; Betreuer: Rebecca Wade." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://nbn-resolving.de/urn:nbn:de:bsz:16-heidok-273745.

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Henderson, Ian Matthew John. "A fluorescence study of the kinetics of the sarcoplasmic reticulum Ca'2'+-ATPase." Thesis, University of Southampton, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296060.

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19

Das, Lipsa, Todd A. Anderson, Jaime M. C. Gard, Isis C. Sroka, Stephanie R. Strautman, Raymond B. Nagle, Colm Morrissey, Beatrice S. Knudsen, and Anne E. Cress. "Characterization of Laminin Binding Integrin Internalization in Prostate Cancer Cells." WILEY, 2017. http://hdl.handle.net/10150/623537.

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Laminin binding integrins 6 (CD49f) and 3 (CD49c) are persistently but differentially expressed in prostate cancer (PCa). Integrin internalization is an important determinant of their cell surface expression and function. Using flow cytometry, and first order kinetic modeling, we quantitated the intrinsic internalization rates of integrin subunits in a single cycle of internalization. In PCa cell line DU145, 6 integrin internalized with a rate constant (k(actual)) of 3.25min(-1), threefold faster than 3 integrin (1.0min(-1)), 1.5-fold faster than the vitronectin binding v integrin (CD51) (2.2min(-1)), and significantly slower than the unrelated transferrin receptor (CD71) (15min(-1)). Silencing of 3 integrin protein expression in DU145, PC3, and PC3B1 cells resulted in up to a 1.71-fold increase in k(actual) for 6 integrin. The internalized 6 integrin was targeted to early endosomes but not to lamp1 vesicles. Depletion of 3 integrin expression resulted in redistribution of 64 integrin to an observed cell-cell staining pattern that is consistent with a suprabasal distribution observed in epidermis and early PIN lesions in PCa. Depletion of 3 integrin increased cell migration by 1.8-fold, which was dependent on 61 integrin. Silencing of 6 integrin expression however, had no significant effect on the k(actual) of 3 integrin or its distribution in early endosomes. These results indicate that 3 and 6 integrins have significantly different internalization kinetics and that coordination exists between them for internalization. J. Cell. Biochem. 118: 1038-1049, 2017.

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Tolentino, Timothy P. "Measuring ligand diffusivity and receptor binding kinetics within a cell membrane contact area." Thesis, Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/20297.

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Teerapanich, Pattamon. "Fluorescence-based nanofluidic biosensor platform for real-time measurement of protein binding kinetics." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30239/document.

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L'analyse cinétique d'interactions de protéines offre une multitude d'informations sur les fonctions physiologiques de ces molécules au sein de l'activité cellulaire, et peut donc contribuer à l'amélioration des diagnostics médicaux ainsi qu'à la découverte de nouveaux traitements thérapeutiques. La résonance plasmonique de surface (SPR) est la technique de biodétection optique de référence pour les études cinétiques d'interaction de molécules biologiques. Si la SPR offre une détection en temps réel et sans marquage, elle nécessite en revanche des équipements coûteux et sophistiqués ainsi que du personnel qualifié, limitant ainsi son utilisation au sein de laboratoires de recherche académiques. Dans ces travaux de thèse, nous avons développé une plateforme de biodétection basée sur l'utilisation de nanofentes biofonctionnalisées combinées avec une détection par microscopie à fluorescence. Ce système permet l'observation en temps réel d'interactions protéines-protéines et la détermination des constantes cinétiques associées, avec des temps de réponse optimisés et une excellente efficacité de capture. La fonctionnalité du système a été démontrée par l'étude des cinétiques d'interaction de deux couples modèles de différentes affinités : le couple streptavidine/biotine et le couple IgG de souris/anti-IgG de souris. Une très bonne cohérence entre les constantes cinétiques extraites, celles obtenues par des expériences similaires réalisées en SPR et les valeurs rapportées dans la littérature montre que notre approche pourrait être facilement applicable pour l'étude cinétique d'interactions de protéines avec une sensibilité allant jusqu'au pM, sur une large gamme de constantes de dissociation. De plus, nous avons intégré un générateur de gradient de concentrations microfluidique en amont de nos nanofentes, permettant ainsi des mesures simultanées de cinétiques d'interactions à différentes concentrations d'analyte en une seule expérience. Ce système intégré offre de nombreux avantages, tels qu'une réduction de la consommation des réactifs et des temps d'analyse par rapport aux approches séquentielles classiques. Cette technologie innovante pourrait ainsi être un outil précieux non seulement pour les domaines du biomédical et de la médecine personnalisée mais aussi pour la recherche fondamentale en chimie et biologie
Kinetic monitoring of protein-protein interactions offers fundamental insights of their cellular functions and is a vital key for the improvement of diagnostic tests as well as the discovery of novel therapeutic drugs. Surface plasmon resonance (SPR) is an established biosensor technology routinely used for kinetic studies of biomolecular interactions. While SPR offers the benefits of real-time and label-free detection, it requires expensive and sophisticated optical apparatus and highly trained personnel, thus limiting the accessibility of standard laboratories. In this PhD project, we have developed an alternative and cost-effective biosensor platform exploiting biofunctionalized nanofluidic slits, or nanoslits, combined with a bench-top fluorescence microscope. Our approach enables the visualization of protein interactions in real-time with the possibility to determine associated kinetic parameters along with optimized response times and enhanced binding efficiency. We have demonstrated the effectiveness of our devices through kinetic studies of two representative protein-receptor pairs with different binding affinities: streptavidin-biotin and mouse IgG/anti-mouse IgG interactions. Good agreement of extracted kinetic parameters between our device, SPR measurements and literature values indicated that this approach could be readily applicable to study kinetics of protein interactions with sensitivity down to 1 pM on a large scale of dissociation constants. In addition, we have incorporated a microfluidic gradient generator to our validated nanoslit device, which has allowed one-shot parallel kinetic measurements to be realized in a single-experiment. This integrated system provides advantages of diminished material consumption and analysis time over the conventional kinetic assays. We believe that this innovative technology will drive future advancements not only in the discipline of biomedical and personalized medicine, but also in basic chemical/biological research

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Sivaprasad, Umasundari. "The mechanism of lactogen receptor binding by human prolactin." Connect to this title online, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1054499303.

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Thesis (Ph. D.)--Ohio State University, 2003.
Title from first page of PDF file. Document formatted into pages; contains xiii, 133 p.; also includes graphics (some col.) Includes bibliographical references (p. 124-133). Available online via OhioLINK's ETD Center

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Liu, Chang. "Localized Surface Plasmon Resonance Biosensors for Real-Time Biomolecular Binding Study." FIU Digital Commons, 2013. http://digitalcommons.fiu.edu/etd/837.

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Surface Plasmon Resonance (SPR) and localized surface plasmon resonance (LSPR) biosensors have brought a revolutionary change to in vitro study of biological and biochemical processes due to its ability to measure extremely small changes in surface refractive index (RI), binding equilibrium and kinetics. Strategies based on LSPR have been employed to enhance the sensitivity for a variety of applications, such as diagnosis of diseases, environmental analysis, food safety, and chemical threat detection. In LSPR spectroscopy, absorption and scattering of light are greatly enhanced at frequencies that excite the LSPR, resulting in a characteristic extinction spectrum that depends on the RI of the surrounding medium. Compositional and conformational change within the surrounding medium near the sensing surface could therefore be detected as shifts in the extinction spectrum. This dissertation specifically focuses on the development and evaluation of highly sensitive LSPR biosensors for in situ study of biomolecular binding process by incorporating nanotechnology. Compared to traditional methods for biomolecular binding studies, LSPR-based biosensors offer real-time, label free detection. First, we modified the gold sensing surface of LSPR-based biosensors using nanomaterials such as gold nanoparticles (AuNPs) and polymer to enhance surface absorption and sensitivity. The performance of this type of biosensors was evaluated on the application of small heavy metal molecule binding affinity study. This biosensor exhibited ~7 fold sensitivity enhancement and binding kinetics measurement capability comparing to traditional biosensors. Second, a miniaturized cell culture system was integrated into the LSPR-based biosensor system for the purpose of real-time biomarker signaling pathway studies and drug efficacy studies with living cells. To the best of our knowledge, this is the first LSPR-based sensing platform with the capability of living cell studies. We demonstrated the living cell measurement ability by studying the VEGF signaling pathway in living SKOV-3 cells. Results have shown that the VEGF secretion level from SKOV-3 cells is 0.0137 ± 0.0012 pg per cell. Moreover, we have demonstrated bevacizumab drug regulation to the VEGF signaling pathway using this biosensor. This sensing platform could potentially help studying biomolecular binding kinetics which elucidates the underlying mechanisms of biotransportation and drug delivery.

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Lukac, I. "The development and assessment of computational approaches to the thermodynamics and kinetics of binding." Thesis, Liverpool John Moores University, 2017. http://researchonline.ljmu.ac.uk/5502/.

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Molecular recognition refers to the interaction between two or more molecules through complementary noncovalent bonding, for example, via hydrogen bonding, electrostatic interactions, van der Waals forces or hydrophobic forces. Molecular recognition plays an important role in biology and mediates interactions between receptors and ligands, antigens and antibodies, nucleic acids and proteins, proteins and proteins, enzymes and substrates, and nucleic acids with each other. Many cellular processes are governed by a group of proteins acting in a coordinated manner; such complicated mechanisms are closely regulated: changes in the populations of particular complexes or changes in concentrations of the products of protein mediated reactions can switch cells from one state to another (from replication to apoptosis, for example). These small variations in molecular populations are caused by very delicate differences in the thermodynamics or kinetics of reactions. This implies that in order to understand not only biological systems in terms of their molecular components, but also to be able to predict and model system response to stimuli (whether it is a natural substrate or a drug), characterisation of the thermodynamic and kinetic components of the binding process is of paramount importance. This combined computational-experimental project was focused on the development of new computational approaches able to predict the enthalpic component of ligand binding, using quantum mechanics. A concept of ‘theoceptors’ was developed, which are theoretical receptors constructed by computing the optimal geometry of ligands binding in the receptor. This project was supported by AstraZeneca, and it included an industrial placement in the Structural and Biophysical Sciences area, where the experimental data was generated to characterise the thermodynamics and kinetics of binding of a range of ligands to two biological targets, using two experimental techniques, isothermal titration calorimetry and surface plasmon resonance. The findings contribute greatly to the process currently underway of expanding our understanding of the relevance of both of these aspects of biochemistry to drug discovery.

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Shimizu, Yuji. "Studies on the binding kinetics and signaling biases of drugs targeting seven-transmembrane receptors." Kyoto University, 2018. http://hdl.handle.net/2433/230981.

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Done, Sarah Helen. "Structural studies of penicillin acylase." Thesis, University of York, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.481793.

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Nauli, Sehat. "Folding kinetics and redesign of Peptostreptococcal protein L and G /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/9237.

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Jackson, Beckford Shirlene R. "Biophysical Characterization of the Binding of Homologous Anthraquinone Amides to DNA." Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/chemistry_diss/70.

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The synthesis of four homologous anthraquinones (AQ I-IV) bearing increasing lengths of polyethylene glycol (PEG) side chains and their binding to AT- and GC-rich DNA hairpins are reported. The molecules were designed such that the cationic charge is at a constant position and the ethylene glycol units chosen to allow significant increases in size with minimal changes in hydrophobicity. The mode and affinity of binding were assessed using circular dichroism (CD), nuclear magnetic resonance (NMR), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC). The binding affinity decreased as the AQ chain length increased along the series with both AT- and GC-rich DNA. ITC measurements showed that the thermodynamic parameters of AQ I-IV binding to DNA exhibited significant enthalpy-entropy compensation. The enthalpy became more favorable while the entropy became less favorable. The correlation between enthalpy and entropy may involve not only the side chains, but also changes in the binding of water and associated counterions and hydrogen bonding. The interactions of AQ I-IV with GC-rich DNA have been studied via molecular dynamics (MD) simulations. The geometry, conformation, interactions, and hydration of the complexes were examined. As the side chain lengthened, binding to DNA reduced the conformational space, resulting in an increase in unfavorable entropy. Increased localization of the PEG side chain in the DNA groove, indicating some interaction of the side chain with DNA, also contributed unfavorably to the entropy. The changes in free energy of binding due to entropic considerations (-3.9 to -6.3 kcal/mol) of AQ I-IV were significant. The kinetics of a homologous series of anthraquinone threading intercalators, AQT I-IV with calf thymus DNA was studied using the stopped-flow. The threading mechanisms of the anthraquinones binding to DNA showed sensitivity to their side chain length. Fitting of the kinetic data led to our proposal of a two step mechanism for binding of AQT I, bearing the shortest side chain, and a three step mechanism for binding of the three longer homologs. Binding involves formation of an externally bound anthraquinone-DNA complex, followed by intercalation of the anthraquinone for AQT I-IV, then isomerization to another complex with similar thermodynamic stability for AQT II-IV.

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Brims, Daniel R. "Kinetics of ligand binding and drug response in a whole cell system using flow injection analysis /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/8614.

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Huxley, Lucinda. "Kinetics and specificity of nicotinamide nucleotide binding to the dIII component of transhydrogenase from Rhodospirillum Rubrum." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/1441/.

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Transhydrogenase is an enzyme located in the cytoplasmic membrane of bacteria or the inner membrane of animal mitochondria. Using the energy of the proton electrochemical gradient (Δp), transhydrogenase translocates protons across the membrane whilst undergoing its redox reaction, in which hydride ion equivalents are transferred from NADH to NADP+ producing NAD+ and NADPH. Transhydrogenase comprises three components; dI binds NA(H), dIII binds NADP(H) and dII spans the membrane. Transhydrogenase is thought to function by way of a binding-change mechanism, which involves “open” and “occluded” conformations of the enzyme. In the open conformation, nucleotides can readily bind and dissociate from the enzyme but the hydride transfer reaction is blocked. In the occluded conformation, hydride transfer is permitted but the binding and release of nucleotides is blocked. Hydride transfer and proton translocation are coupled. The coupling is not well understood due to the lack of structural information about the membrane-spanning dII component. However, it is believed to involve conformational changes of the enzyme, particularly the dII and dIII components, resulting in the switch between the open and occluded conformations. Enzyme assays and tryptophan fluorescence experiments using apo-dIII in complex with dI revealed two features: Firstly, the binding of NADP(H) to dIII is very slow and is probably limited by the conversion from the occluded to the open conformation. Since the switch between the occluded and open conformations is thought to be central in the coupling of hydride transfer and proton translocation, the results presented here give an insight into the binding-change mechanism of transhydrogenase. Secondly, NAD(H) is able to slowly bind into the NADP(H)-binding site of dIII (the “wrong” site). This brought into question the specificity of the dIII component of transhydrogenase for NADP(H). The significance and likelihood of NAD(H) binding to dIII in the intact enzyme in the living cell are discussed.

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Svetlanova, Anna. "Thermodynamics and Kinetics of Small Molecule Binding to [Cyclopentadienyl-Ru-NO] and [Rh-CO] Electrophilic Centers." DigitalCommons@USU, 1996. https://digitalcommons.usu.edu/etd/7188.

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This work is concentrated on the thermodynamic and kinetic aspects of water, alcohols, alkyl halides, ethers, and lactones bound and activated by the electrophilic [Cp'Ru(N0)] +2 and [Cp’Ru (NO)(CH3)] + centers (Cp' = cyclopentadienyl group). Counterions in these systems include OSO2CF3- (OTf-) and [(3, 5-(CF3)2C6H3)4B]- ([BAr4']-). The displacement of OTf- in Cp'Ru(N0) (0Tf)2 by H20 in dichloromethane is exothermic but entropically unfavorable due to the required reorganization of the solvent cage around released triflate ions. Thermodynamic parameters are also determined for OTf displacement by chloride and tetrahydrofuran (THF) using the 19F nuclear magnetic resonance (NMR) spectroscopy. The conversion of the [Cp’Ru (NO)(OH2)2] +2 to [Cp’Ru (NO)(μ-OH)} 2 +2 in aqueous solutions is characterized thermodynamically and kinetically by potentiometric and NMR methods. The results of the study of rhodium triflato complex trans- [Rh (CO)(PPh3)2(OTf)] show that OTf coordinates to the metal center in wet dichloromethane solutions, but the compound crystallizes as a water-coordinated triflate salt trans- [Rh (CO)(PPh3)2(OH2)] [OTf]. Thermodynamic parameters for alcohol (methanol, ethanol, isopropanol) binding to the Cp*Ru(N0) (0Tf)2 are determined from the 19F NMR spectroscopic data. The kinetics of the oxidation of alcohols to aldehydes or ketones via Ru (II) >>> Ru (0) redox process is studied by NMR methods. The results of the study support {3-hydrogen elimination mechanism, comprising one of the very few mechanistic investigations on reactions of this kind. Alkyl iodides are found to bind to the [Cp*Ru (NO)(CH3)] + fragment via displacement of a THF ligand in the presence of a BAr4 •-counterion, forming alkyl halide complexes that convert to [Cp’Ru (NO)(μ-I)]2+2. The mixed ruthenium-chromium complex [CpCr (NO)2(μ-I) (Ru (Cp’) (NOW is characterized as primarily a [Ru-I >> Cr] system as opposed to a [Ru << I-Cr] model. The complex [Cp*Ru (NO)(CH3) (THF)] is found to catalyze aerobic oxidation of THF to -y-butyrolactone. The new -y-butyrolactone ruthenium complex is isolated and characterized by X-ray methods in the solid state. The mechanism of catalytic oxidation is studied by 18O-labeled infrared spectroscopic methods. Radical decomposition of the intermediate hydroperoxy-tetrahydrofuran gives 1, 6-diol-diformate [CH(O)-(CH2)6-CH(O)]. The radical mechanism for the catalytic oxidation of THF is proposed.

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Wu, Guanmin Richmond Michael G. "Synthesis characterization, and kinetics of isomerization, C-H and P-C bond activation for unsaturated diphosphine-coordinated triosmium carbonyl clusters." [Denton, Tex.] : University of North Texas, 2008. http://digital.library.unt.edu/permalink/meta-dc-6037.

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Harris, Derek Franklin. "A Universal Mechanism for N2 Binding to and Differing Reactivity of the E4(4H) State of Mo-, V-, and Fe-Nitrogenases." DigitalCommons@USU, 2019. https://digitalcommons.usu.edu/etd/7556.

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As a basic building block in many biological molecules, the element nitrogen (N) is essential for life. Dinitrogen (N2) is abundant in Earth’s atmosphere, but this form is biologically unavailable. To be biologically available, N2 must undergo a reduction reaction to the fixed form, ammonia (NH3). The industrial Haber-Bosch process, which accounts for approximately 50% of the worlds fixed nitrogen, uses energy from fossil fuels to achieve high pressures and temperatures to catalyze the reaction. The energy used by Haber-Bosch accounts for approximately 2% of the world’s annual supply. The remainder of fixed nitrogen is produced biologically by nitrogen fixing microorganisms (diazotrophs), utilizing nitrogenase enzymes. Nitrogenase enzymes catalyze the reduction at ambient temperature and pressure, deriving the necessary energy from the energy rich molecule adenosine triphosphate (ATP). The focus of this dissertation is enriching our understanding of how nitrogenase enzymes can catalyze this crucial reaction under ambient conditions. This, of course, leads to a better understanding of biological nitrogen fixation, but also reveals the strategies that nature has evolved which can inform on the development of cleaner more efficient industrial processes.

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Liang, Yizhi. "Study of The Mode of Action of Bacillus thuringiensis Delta- Endotoxin by Gene Manipulation and Binding Kinetics /." The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487932351056975.

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Yang, Li. "Kinetic Studies on C‐h Bond Activation in the Reaction of Triosmium Clusters with Diphosphine and Amidine Ligands." Thesis, University of North Texas, 2014. https://digital.library.unt.edu/ark:/67531/metadc699850/.

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The reaction of 1-(diphenylphosphino)-2-(diphenylphosphito)benzene (PP*) and Os3(CO)10(ACN) has been investigated. A combined experimental and computational study on the isomerization of 1,2-Os3(CO)10[μ-1,2-Ph2P(C6H4)P(OPh)2] (A) and 1,1-Os3(CO)10[μ-1,2-Ph2P(C6H4)P(OPh)2] (B) and reversible ortho-metalation exhibited by the triosmium cluster B are reported. The subsequent conversion of cluster B to the hydrido cluster HOs3(CO)9[μ-1,2-PhP(C6H4-η1)C6H4P(OPh)2] (E) and the benzyne-substituted cluster HOs3(CO)8(µ3-C6H4)[μ-1,2-PhP(C6H4)P(OPh)2] (N) has been established. All of these new clusters have been isolated and fully characterized in solution by IR and NMR spectroscopy; in addition, X-ray diffraction analyses have been performed on the clusters A, B, J, and N. The ortho-metalation reaction that gives cluster E is shown to be reversible, and the mechanism has been probed using selectively deuterated PP* isotopomers. Kinetic and thermodynamic isotope data, in conjunction with DFT calculations, are presented that support the existence of an intermediate unsaturated cluster in the ortho-metalation reaction. Due to interest in the coordination chemistry of formamidines, the non-symmetric amidine ligands PhNC(Me)NHPri, PhNC(Et)NHPri, and (2,4,6-Me3C6H2)NC(Me)NHPri, have been synthesized, and their reaction with Os3(CO)10(MeCN)2 has been investigated. Of the twelve new clusters prepared in section, seven have been structurally characterized by X-ray crystallography.

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Yang, Li. "Syntheses, X-ray Diffraction Structures, and Kinetics on New Formamidinate-Substituted Triosmium Clusters." Thesis, University of North Texas, 2010. https://digital.library.unt.edu/ark:/67531/metadc33217/.

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The reaction between the formamidine ligand PriN=CHNHPri and the activated cluster Os3(CO)10(MeCN)2 has been studied. A rapid reaction is observed at room temperature, yielding the hydride clusters HOs3(CO)9[μ-OCNPriC(H)NPri] and HOs3(CO)10[μ-NPriC(H)NPri] as the principal products. The spectroscopic data and X-ray diffraction structures of those formamidinate-substituted clusters will be present. The thermal reactivity of the clusters has been investigated, with the face-capped cluster HOs3(CO)9[μ-NPriC(H)NPri] found as the sole observable product. The relationship between these three clusters has been established by kinetic studies, the results of which will be discussed.

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Bhagdikar, Divyaa. "Comparative analysis of ligand binding properties of transcriptional and translational S-box riboswitches." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1593683073097626.

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38

Zhang, Fang. "Two-dimensional binding kinetics of intracellular adhesion molecule-1 for αL inserted domains and β₂ integrins at different conformational states." Thesis, Georgia Institute of Technology, 2004. http://hdl.handle.net/1853/9452.

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Chen, Wei. "The force regulation on binding kinetics and conformations of integrin and selectins using a bio-membrane force probe." Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/33814.

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Cell adhesion plays an important role in inflammation and immunological responses. Adhesion molecules (e.g., selectins and integrins) are key modulators in mediating these cellular responses, such as leukocyte trafficking under shear stress. In this thesis, we use a bio-membrane force probe (BFP) to study force regulation on kinetics and conformations of selectin and LFA-1 integrin. A new BFP was built up, and a new assay, using thermal fluctuation of the BFP, was developed and used to monitoring selectins and their ligands association and dissociations. The new BFP was also used to investigate the force and force history dependence of selectin-ligand interactions. We found tri-phasic transition of force-dependent off-rates and force-history dependence of selectin/ligaind interactions. The BFP was also used to characterize force-dependent lifetimes of the LFA-1-ICAM-1 interaction. We found that LFA-1/ICAM-1 bonds behaved as catch bond and that LFA-1-ICAM-1's catch bonds were abolished blocking the downward movement of αA domain α7 helix. Finally, the BFP was applied to dynamically probe the global conformational changes of LFA-1 and to characterize force-regulated transitions among different conformational states on a living cell. We observed dynamic transitions of LFA-1 between extended and bent conformations on living cells. The observed average distance change of LFA-1's extensions was about 18nm, while that of the bending was only about 14nm. We also found that forces could facilitate extension but they slow down the bending of LFA-1. The observed transition time of extension was less than 0.1s, while that of contraction was longer than 0.2s. Our observations here are the first in-situ evidence to demonstrate how integrins dynamically transit different conformations and how force regulates these transitions.

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Berger, Benedict-Tilman [Verfasser], Stefan [Akademischer Betreuer] Knapp, Susanne [Akademischer Betreuer] Müller-Knapp, Stefan [Gutachter] Knapp, and Eugen [Gutachter] Proschak. "Structural mechanisms of binding kinetics / Benedict-Tilman Berger ; Gutachter: Stefan Knapp, Eugen Proschak ; Stefan Knapp, Susanne Müller-Knapp." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2020. http://d-nb.info/1221669206/34.

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Modi, Sweta. "The Critical Role of Mechanism-Based Models for Understanding and Predicting Liposomal Drug Loading, Binding and Release Kinetics." UKnowledge, 2013. http://uknowledge.uky.edu/pharmacy_etds/19.

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Liposomal delivery systems hold considerable promise for improvement of cancer therapy provided that critical formulation design criteria can be met. The main objective of the current project was to enable quality by design in the formulation of liposomal delivery systems by developing comprehensive, mechanism-based mathematical models of drug loading, binding and release kinetics that take into account not only the therapeutic requirement but the physicochemical properties of the drug, the bilayer membrane, and the intraliposomal microenvironment. Membrane binding of the drug affects both drug loading and release from liposomes. The influence of bilayer composition and phase structure on the partitioning behavior of a model non-polar drug, dexamethasone, and its water soluble prodrug, dexamethasone phosphate, was evaluated. Consequently, a quantitative dependence of the partition coefficient on the free surface area of the bilayer, a property related to acyl chain ordering, was noted. The efficacy of liposomal formulations is critically dependent on the drug release rates from liposomes. However, various formulation efforts to design optimal release rates are futile without a validated characterization method. The pitfalls of the commonly used dynamic dialysis method for determination of apparent release kinetics from nanoparticles were highlighted along with the experimental and mathematical approaches to overcome them. The value of using mechanism-based models to obtain the actual rate constant for nanoparticle release was demonstrated. A novel method to improve liposomal loading of poorly soluble ionizable drugs using supersaturated drug solutions was developed using the model drug AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin), a poorly soluble camptothecin analogue. Enhanced loading with a drug to lipid ratio of 0.17 was achieved and the rate and extent of loading was explained by a mathematical model that took into account the chemical equilibria inside and outside the vesicles and the transport kinetics of various permeable species across the lipid bilayer and the dialysis membrane. Tunable liposomal release kinetics would be highly desirable to meet the varying therapeutic requirements. A large range of liposome release half-lives from 1 hr to 892 hr were obtained by modulation of intraliposomal pH and lipid composition using dexamethasone phosphate as a model ionizable drug. The mathematical models developed were successful in accounting for the change in apparent permeability with change in intraliposomal pH and bilayer free surface area. This work demonstrates the critical role of mechanism-based models in design of liposomal formulations.

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Kwok, Ka Cheung. "Measuring binding kinetics of ligands with tethered receptors by fluorescence polarization complemented with total internal reflection fluorescence microscopy." HKBU Institutional Repository, 2010. https://repository.hkbu.edu.hk/etd_oa/18.

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The study of the binding between estrogen receptors (ER) and their ligands in vitro has long been of interest mainly because of its application in anti-estrogen drug discovery for breast cancer treatment as well as in the screening of environmental contaminants for endocrine disruptors. Binding strength was conventionally quantified in terms of equilibrium dissociation constant (KD). Recently, emphasis is shifting towards kinetics rate constants, and off-rate (koff) in particular. This thesis reported a novel method to measure such binding kinetics based on fluorescence polarization complemented with total internal reflection fluorescence (FP-TIRF). It used tethered receptors in a flow cell format. For the first time, the kinetics rate constants of the binding of full-length human recombinant ERα with its standard ligands were measured. koff was found to range from 1.3 10-3 to 2.3 10-3 s-1. kon ranged from 0.3 105 to 11 105 M-1 s-1. The method could also be used to screen potential ligands. Motivated by recent findings that ginsenosides might be functional ligands of nuclear receptors, eleven ginsenosides were scanned for binding with ER and peroxisome proliferator-activated receptor gamma (PPAR). None of the ginsenosides showed significant binding to ER, but Rb1 and 20(S)-Rg3 exhibited significant specific binding with PPAR.

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43

Zhang, Fang. "Two-dimensional binding kinetics of intracellular adhesion molecule-1 for [alpha]L inserted domains and [beta]₂ integrins at different conformational states." Available online, Georgia Institute of Technology, 2004:, 2004. http://etd.gatech.edu/theses/available/etd-06072004-131425/unrestricted/zhang%5Ffang%5F200405%5Fms.pdf.

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Johansson, Fredrik. "Microscale measurement of kinetic binding properties of monoclonal antibodies in solution using Gyrolab." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-155575.

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The number of monoclonal antibodies approved for therapeutic use has increased rapidlyover the last decade. As a consequence, precise and robust kinetic characterization techniquesare crucial in order to select the best suitable candidates. A kinetic characterization methodwas developed in Gyrolab with automated sample transfers. The characterization wasperformed in solution in a mixing CD, containing an integrated nanoliter mixing chamberwith affinity binding columns. Association rate constants were determined for four anti-TSHantibodies with values ranging from 3x105 M-1s-1 to 10x105 M-1s-1. The antibodies wereranked according to kass. Reproducibility

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45

Mabrouki, Ridha Ben Mohsen. "Drift Tube Ion Mobility Measurements for Thermochemistry, Kinetics and Polymerization of Cluster Ions." VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd/1165.

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In this work, the Drift Tube Ion Mobility technique is used to study the hydrophobic hydration and solvation of organic ions and measure the thermochemistry and kinetics of ion-molecule reactions. Furthermore, an exploratory study of the intracluster polymerization of isoprene will be presented and discussed. The ion hydration study is focused on the C3H3+ cation1 and Pyridine▪+ radical cation.2 The chemistry of the cyclic C3H3+ cation1 has received considerable attention and continues to be an active area of research.3-7 The binding energies of the first 5 H2O molecules to c-C3H3+ were determined by equilibrium measurements. The measured binding energies of the hydrated clusters of 9-12 kcal/mol are typical of carbon-based CH+X hydrogen bonds. The ion solvation with the more polar CH3CN molecules results in stronger bonds consistent with the increased ion-dipole interaction. Ab initio calculations show that the lowest energy isomer of the c-C3H3+(H2O)4 cluster consists of a cyclic water tetramer interacting with the c-C3H3+ ion, which suggests the presence of orientational restraint of the water molecules consistent with the observed large entropy loss. The c-C3H3+ ion is deprotonated by 3 or more H2O molecules, driven energetically by the association of the solvent molecules to form strongly hydrogen bonded (H2O)nH+ clusters. The kinetics of the associative proton transfer (APT) reaction C3H3+ + nH2O → (H2O)nH+ + C3H2 exhibits an unusually steep negative temperature coefficient of k = cT(sup>63±4 (or activation energy of -32 ± 1 kcal mol-1). The behavior of the C3H3+/water system is exactly analogous to the benzene+ /water system8,9, suggesting that the mechanism, kinetics and large negative temperature coefficients may be general to multibody APT reactions. These reactions can become fast at low temperatures, allowing ionized polycyclic aromatics to initiate ice formation in cold astrochemical environments.The solvation energies of the pyridine+ radical cation by 1- 4 H2O molecules are determined by equilibrium measurements in the drift cell. The binding energies of the pyridine+(H2O)n clusters are similar to the binding energies of protonated pyridineH+(H2O)n clusters that involve NH+∙∙OH2 bonds, and different from those of the solvated radical benzene+(H2O)n ions that involve CHδ+∙∙OH2 bonds. These relations indicate that the observed pyridine+ ions have the distonic C5H4NH+ structure that can form NH+∙∙OH2 bonds. The observed thermochemistry and ab initio calculations show that these bonds are not affected significantly by an unpaired electron at another site of the ion. The distonic structure is also consistent with the reactivity of pyridine+ in H atom transfer, intra-cluster proton transfer and deprotonation reactions. The results present the first measured stepwise solvation energies of distonic ions, and demonstrate that cluster thermochemistry can identify distonic structures.The gas phase clustering of small molecules around the hydronium ion is of fundamental interest and is relevant to important atmospheric and astrophysical processes. In this work, the equilibrium constants for the formation of the H3O+(X)n clusters with X = H2, N2 and CO and n = 1-3 at different temperatures are measured using the drift tube technique10. The arrival time distributions (ATDs) of the injected H3O+ and the H3O+(X)n clusters formed inside the cell are measured under equilibrium conditions. The resulting binding energies for the addition of one and two hydrogen molecules are similar [3.4 and 3.5 kcal/mol, respectively). For the N2 clustering with n = 1-3, the measured binding energies are 7.9, 6.9 and 5.4 kcal/mol, respectively. The clustering of CO on the H3O+ ion exhibits a relatively strong binding energy (11.5 kcal/mol) consistent with the dipole moment and polarizability of the CO molecule. Theoretical calculations of the lowest energy structures are correlated to the experimental results. Finally, intracluster polymerization leading to the formation of covalent bonded oligomer ions has been investigated following the ionization of neutral isoprene clusters. The results indicate that isoprene dimer cation has a structure similar to that of the limonene radical cation. Mass-selected mobility and dissociation studies also indicate that the larger isoprene cluster ions have covalent bonded structures. The conversion of molecular clusters into size-selected oligomers is an important process not only for detailed understanding of the early stages of polymerization but also for practical applications such as the formation of new polymeric materials with controlled and unusual properties.

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卓文森 and Man-sum Cheuk. "Effects of sodium pyrophosphate and pH on the kinetics of iron releasefrom the N- and C-terminal binding sites of ovotransferrin." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1988. http://hub.hku.hk/bib/B31208551.

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Cheuk, Man-sum. "Effects of sodium pyrophosphate and pH on the kinetics of iron release from the N- and C-terminal binding sites of ovotransferrin /." Hong Kong : University of Hong Kong, 1988. http://sunzi.lib.hku.hk/hkuto/record.jsp?B12434838.

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48

Zhang, Yanyan. "Investigation of SH2 Domains: Ligand Binding, Structure and Inhibitor Design." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1259766230.

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49

Parry, Damian. "Restriction endonuclease EcoRV : use of base analogues to investigate catalysis and binding employing single turn-over kinetics and fluorescent techniques." Thesis, University of Newcastle Upon Tyne, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263130.

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50

Ferrer, Jorge M. 1976. "Combined optical trapping and single molecule fluorescence to study the force-dependent binding kinetics between filamentous actin and its partners." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/27059.

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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2004.
Includes bibliographical references (p. 75-77).
Actin filaments are a major constituent of the cytoskeleton in most eukaryotic cells. They function as a connection between the cell body to the focal adhesions in order to transmit forces into and out of the cell. During the force transduction process, many proteins bind to actin filaments in order to initiate a signaling cascade that reaches the cell nucleus. However, the effects of forces in the binding kinetics between actin filaments and actin binding proteins are unknown. This work proposes an experimental setup to study the force-dependent binding kinetics of such proteins at the single molecule level by using an instrument that combines optical trapping with single molecule fluorescence. The main focus of this work was the design and construction of the experimental equipment. The results show position detection capabilities with a resolution of 5 nm. Also, the trap stiffness recorded was in the order of 0.05 pN/nm. With the combination of position and trap stiffness, the force resolution of the instrument is about 0.25 pN. Also, a photobleaching event for a single dye molecule was recorded, proving the single molecule fluorescence capabilities. In addition, a complete experimental assay is described in order to perform studies on how force application affects the binding of actin and actin binding proteins.
by Jorge M. Ferrer.
S.M.

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