Dissertations / Theses on the topic 'Conformation Dynamics'
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Link, Justin J. "Ultrafast Protein Conformation Dynamics." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1230584570.
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Zang, Chen. "Ultrafast Spectroscopic Study of Protein Conformation Dynamics and Hydration Dynamics." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299481658.
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Zhang, Lyndon N. (Lyndon Nuoxi). "Conformation and dynamics of the mammalian chromosome." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103441.
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Thesis: S.M., Massachusetts Institute of Technology, Department of Biology, 2016.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (pages 29-30).
The control of transcription represents a fundamental, initial mechanism by which the regulation of gene expression is implemented. However, while much research has been done on the biochemistry and cellular function of transcription, comparatively little is known on the dynamics of transcriptional mechanisms, their impact on chromatin structure, and concomitant functional consequences. Employing chromatin immunoprecipitation measurements, we report progress towards this goal. We characterize the ensemble chromosome conformation in mouse embryonic stem cells, by measuring interaction, or contact, probabilities between distal genomic loci. We map and describe chromosome loops, consisting of two interacting CTCF sites co-bound by cohesin, that maintain the expression of genes known to promote cell identity, and restrict the expression of genes specifying repressed developmental lineages.
by Lyndon N. Zhang.
S.M.
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Wooten, E. Wrenn. "Structure, conformation and dynamics of N-linked oligosaccharides." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.253421.
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Winsborrow, BeAtrice G. "Glycolipid conformation and dynamics in model and biological membranes." Thesis, University of Ottawa (Canada), 1993. http://hdl.handle.net/10393/6811.
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The focus of this dissertation has been the biophysical analysis of two related research subjects: a model membrane glycolipid system and glycolipid-rich biomembranes. The objective of the model system study was to provide a biological understanding of the molecular conformation and dynamics at the membrane surface. The biomembrane project is in the first stages of development where the immediate goal is to observe the structure and phase behaviour of cyanobacterial thylakoid membranes. It has been possible to apply a motional model deduced for the glycerol C3$\sp\prime$ position of 1,2-di-O-tetradecyl-3-O-$(\beta$-D-glucopyranosyl)-sn-glycerol $(\beta$-DTGL) in the gel state not only to the more fluid liquid crystalline state, but also to the analysis of the glucose head group ($\{$1-$\rm \sp2H\sb1\})$ motions. The above model, however, did not completely simulate the relaxation data of the $\beta$-DTGL glucose head group. Therefore, conformational energy calculations have been used to assess the flexibility of the head group about its glycosidic bond, in a liquid-crystalline membrane matrix. Algal thylakoid membranes are known for their ability to undergo conformational changes during periods of photosynthetic activity. The ultimate goal of the biomembrane project was to use $\sp2$H NMR to study such conformational changes in thylakoid membranes. However, this project is in the first stages of development; the more modest but attainable short term goal was to observe directly the structure and phase behaviour of two strains of cyanobacterial thylakoid membranes, Anacystis nidulans and A. nidulans R2. In both the previous studies and this study, it was found that the heterogeneous systems undergo broad phase transitions and that acyl chain unsaturation lowers the phase transition temperature of the membranes. Although pure digalactosyldiacyglycerol is known to stabilize lamellar membrane phases, it appears as though phosphatidylglycerol (PG) is more influential in stabilizing the lamellar membrane structure of the cyanobacterial thylakoid membranes. This effect was more noticeable for the spectra of extracted lipids; in the absence of protein and with low PG levels, the lipids formed non-lamellar phases at lower temperatures. (Abstract shortened by UMI.)
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Qian, Hong. "Conformation and dynamics of main-chain liquid crystalline polymers." Thesis, Heriot-Watt University, 2004. http://hdl.handle.net/10399/245.
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Dauber-Osguthorpe, Pnina. "Conformation and internal motion of polypeptides : molecular dynamics simulations." Thesis, University of Bath, 1990. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252972.
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Mcgeagh, John David. "Conformation and cooperativity in homodimeric enzymes investigated by molecular dynamics simulations." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.549446.
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Mark, Pekka. "Molecular dynamics studies of water and biomolecules /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-251-5.
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Rönnols, Jerk. "Structure, dynamics and reactivity of carbohydrates : NMR spectroscopic studies." Doctoral thesis, Stockholms universitet, Institutionen för organisk kemi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-92408.
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The main focus of this thesis is on the ring conformations of carbohydrate molecules; how the conformational equilibria and the rates of the associated interconversions are affected by the molecular constitution and their surroundings. The conformational equilibria of a group of amine linked pseudodisaccharides, designed as potential glycosidase inhibitors, comprising α-D-altrosides are described in Chapter 3. The OS2 conformation was largely populated, and the ring conformation was found to depend on the charge of the amine functionality. The conformations of β-D-xylopyranoside derivatives with naphthyl-based aglycones, which are potential anti-cancer agents, are described in chapter 4. Solvent dependent flexibility was observed. Intramolecular hydrogen bonds were concluded to be involved in the stabilization of 1C4 conformers in non-hydrogen bonding solvents of low polarity. Chapter 5 describes the first measurements of the conformational exchange rates of mannuronic acid ester derivatives between the 4C1 and 1C4 conformations, through DNMR measurements. The relative reactivity of glycosyl triflates as electrophiles in glycosylation reactions were investigated with NMR-based competition experiments. In Chapter 6, investigations of ruthenium-catalyzed epimerizations of the allylic alcohols of glycal derivatives, and stereoselective synthesis of esters through a DYKAT protocol, are described. The kinetics of the epimerizations were elaborated through different NMR-spectroscopic methods. Chapter 7 describes additions of NMR chemical shift data of mono- and oligosaccharides to database of the computer program CASPER, and applications thereof.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Submitted. Paper 5: Manuscript.
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Held, Martin [Verfasser]. "Novel concepts to study conformation and association dynamics of biomolecules / Martin Held." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1026992451/34.
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Gagliardi, Simona. "Conformation and dynamics in cyclic and linear polymers by neutron scattering techniques." Thesis, Heriot-Watt University, 2002. http://hdl.handle.net/10399/378.
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Cao, Jin. "Single Molecular Spectroscopy and Atomic Force Manipulation of Protein Conformation and Dynamics." Bowling Green State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1416588612.
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Budi, Bunarta Hendra (Akin), and akin budi@rmit edu au. "On the effects of external stresses on protein conformation." RMIT University. School of Applied Sciences, 2006. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20061116.123431.
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The use of electromagnetic devices such as microwave ovens and mobile phones has certainly brought convenience to our lives. At the same time, the proliferation of said devices has increased public awareness of the potential health hazards. It is generally assumed that there is little or no risk associated with the use of electromagnetic devices, based on the small amount of power associated with those devices. However, case studies on animals indicate that the risk cannot be entirely ruled out. It has long been known that proteins are sensitive to stress, arising from various sources such as temperature, chemical, pressure, and changes in pH condition. In all of these cases, the protein exhibits clear signs of damage and distress, which range from slight unfolding to complete loss of structure. Frequently, the damage to the protein is alleviated by refolding, either by itself or by the aid of molecular chaperones. However, if the damage to the protein is too great, the protein will generally undergo proteolysis. Opinion has been divided over the implication of prolonged use of electromagnetic devices to human health. Studies conducted on animals so far have given conflicting results. The studies on the separate components, electric and magnetic fields, also give inconclusive results. This indicates that our understanding on how electric and magnetic fields interact with biological matter is incomplete. In this project, we use molecular dynamics to explore the behaviour of two forms of insulin chain-B, isolated and monomeric (in the presence of chain-A with all disulfide bonds intact), at ambient conditions and under the influence of various stress. Specifically, we focus our attention to thermal stress and electric field stress. The electric field stress considered in this study takes several forms: static and oscillating with three different frequencies. These fields have strength ranging from 1806 V/m to 109 V/m. By performing molecular dynamics simulations totalling over 500 ns, we have gained valuable insights into the effects of elevated temperature and electric field on insulin chain-B. We observed differences in the damage mechanisms by the application of static electric field and oscillating field. The application of static fields restricts the conformational freedom of a protein, whereas the application of oscillating fields increases the mobility and flexibility of the protein, similar to the effect of thermal stress. Both of these interfere with the normal behaviour of a protein. We have also observed frequency-dependent effects, with low frequency fields having static field-like characteristics in damage mechanism.
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Nam, Sunghyun. "Dynamics of Cyclic and Linear Poly(oxyethylene) and Threading Conformation in Their Blends." Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/14135.
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Chemically identical but topologically different cyclic and linear polymers not only result in marked differences in dynamics, but also lead to unique transport properties of their blends, where cyclic polymers have chances to be threaded onto the linear polymers. This dissertation addresses the effect of ring architecture on dynamics using different time/length scale techniques: self-diffusion coefficients, NMR spin-spin relaxation time (T2) and bulk viscosity.
In deuterated water, synthesized cyclic poly(oxyethylene) (CPOE) (400-1500 g/mol) diffused faster than corresponding linear POE (LPOE) and linear POE dimethyl ether (LPOEDE). However, the self-diffusion coefficients in melts were arranged in the following manner: LPOEDE > CPOE > LPOE, in excellent agreement with T2 and viscosity data, showing topological and chain end effects. Compared to LPOEDE, both CPOE and LPOE had higher activation energies for viscosity with less dependence on the molecular weight.
In the blends of CPOE and LPOE for 900 and 1500 g/mol, the diffusion coefficient and viscosity in melts were higher and lower than the values predicted by a binary mixing rule, respectively. These deviations were attributed to the threading conformation, and the weight fraction of the threaded chains for 1500 g/mol was estimated by a three-term mixing rule. This threading conformation also appeared to influence such important bulk properties as the glass transition and spherulitic growth rate of the blends.
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Sun, Frank Chen Sheiko Sergei. "Molecular visualization of brush-like macromolecules on surfaces molecular conformation and spreading dynamics /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1178.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Mar. 27, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Applied and Materials Sciences." Discipline: Applied and Materials Sciences; Department/School: Applied and Materials Sciences.
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Röblitz, Susanna [Verfasser]. "Statistical error estimation and grid-free hierarchical refinement in conformation dynamics / Susanna Röblitz." Berlin : Freie Universität Berlin, 2009. http://d-nb.info/102346473X/34.
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Mele, Nawel. "Exploring conformation of human fatty acid synthase inhibitors using Replica Exchange Molecular Dynamics." Thesis, University of Southampton, 2017. https://eprints.soton.ac.uk/422135/.
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Human fatty acid synthase (hFAS) is a homodimer multienzyme complex involved in the lipogenesis and catalysis of long-chain fatty acids. hFAS is overexpressed in cancer cells and enhances tumor growth. A recent study reported a new potent and selective inhibitor of the β-ketoacyl reductase (KR) domain of hFAS, GSK2194693. An x-ray crystal structure of this inhibitor bound to the KR domain provides binding mode information regarding the druggable pocket. In this thesis simulations and analysis of the solution-phase conformational ensembles of four inhibitors of the human fatty acid synthase are required. The ensembles are generated using replica exchange enhanced sampling molecular dynamics approaches for two force fields, and analysed using a combination of dihedral and Cartesian space clustering, and principal components analysis. These ensembles are compared to experimental data derived using nuclear magnetic resonance from C4X Discovery to evaluate the convergence of our data and to analyze the influence of the force field on the quality of the sampling. We find that while the simulations are able to identify all the conformations found by NMR, their relative populations are in less satisfactory agreement. The ligandreceptor complex binding modes were also investigated by first identifying conformations of the four compounds with shape and chemical group similarity using clustering and superimposition methodologies. Then, in a ligand preorganization approach to identify if the solution phase conformations obtained from NMR and REMD bind favourably to the receptor binding pocket, the interactions made with hFAS were evaluated keeping the conformations and the receptor rigid. Potential binding modes for the compounds were generated with consistent interactions. Contacts found in the x-ray structure GSK2194069 were highly conserved in the compounds and additional hydrogen bonds were identified. Thus, this study offers valuable information for future drug development and optimization.
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Bruce, Neil John. "Investigating protein conformational change via molecular dynamics simulation." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/investigating-protein-conformational-change-via-molecular-dynamics-simulation(17145939-f643-4b23-bbb9-029cf5489c15).html.
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Accumulation and aggregation of the 42-residue amyloid-[beta] (A[beta]) protein fragment, which originates from the cleavage of amyloid precursor protein by beta and gamma secretase, correlates with the pathology of Alzheimer's disease (AD). Possible therapies for AD include peptides based on the A[beta] sequence, and recently identified small molecular weight compounds designed to mimic these, that interfere with the aggregation of A[beta] and prevent its toxic effects on neuronal cells in culture. Here, we use molecular dynamics simulations to compare the mode of interaction of an active (LPFFD) and inactive (LHFFD) [beta]-sheet breaker peptide with an A[beta] fibril structure from solid state NMR studies. We found that LHFFD had a weaker interaction with the fibril than the active peptide, LPFFD, from geometric and energetic considerations, as estimated by the MM/PBSA approach. Cluster analysis and computational alanine scanning identified important ligand-fibril contacts, including a possible difference in the effect of histidine on ligand-fibril [pi]-stacking interactions, and the role of the proline residue establishing contacts that compete with those essential for maintenance of the inter-monomer [beta]-sheet structure of the fibril. Our results show that molecular dynamics simulations can be a useful way to classify the stability of docking sites. These mechanistic insights into the ability of LPFFD to reverse aggregation of toxic A[beta] will guide the redesign of lead compounds, and aid in developing realistic therapies for AD and other diseases of protein aggregation. We have also performed long explicit solvent MD simulations of unliganded amyloid fibril in three putative protonation states, in order to better understand the energetic and mechanical features of the fibril receptor. Over 100 ns MD simulations, the trajectories where fibril has Glu11 and Glu22 side-chains protonated exhibit the least deviation from the initial solid state NMR structures. Free energy calculations on these rajectories suggest that the weakest fibril interface lies in the lateral rather than transverse direction and that there is little dependence on whether the lateral interface is situated at the edge or middle of the fibril. This agrees with recent reported steered molecular dynamics calculations. Secondly, in an effort to improve the ability of atomistic simulation techniques to directly resolve protein tertiary structure from primary amino acid sequence, we explore the use of a molecular dynamics technique based on swarm intelligence, called SWARM-MD, to identify the native states of two peptides, polyalanine and AEK17, as well as Trp-cage miniprotein. We find that the presence of cooperative swarm interactions significantly enhanced the efficiency of molecular dynamics simulations in predicting native conformation. However, it also is evident that the presence of outlying simulation replicas can adversely impact correctly folded replica structures. By slowly removing the swarm potential after folding simulations, the negative effect of the swarm potential can be alleviated and better agreement with experiment obtained.
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Darian, Eva. "Molecular dynamics simulation study of the stability and conformation of spin-probe labeled DNAs." Morgantown, W. Va. : [West Virginia University Libraries], 1999. http://etd.wvu.edu/templates/showETD.cfm?recnum=1135.
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Thesis (M.S.)--West Virginia University, 1999.Title from document title page. Document formatted into pages; contains ix, 80 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 51-52).
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Guan, Xiao, and 关晓. "NMR approaches to protein conformation and backbone dynamics: studies on hyperthermophilicacylphosphatase and neuropeptide secretoneurin." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44079230.
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Guan, Xiao. "NMR approaches to protein conformation and backbone dynamics studies on hyperthermophilic acylphosphatase and neuropeptide secretoneurin /." Click to view the E-thesis via HKUTO, 2010. http://sunzi.lib.hku.hk/hkuto/record/B44079230.
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Nasreddine, Victor Fuad. "Solid state nuclear magnetic resonance spectroscopy of polymer thin films : chain conformation, dynamics, and morphology." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=83081.
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This dissertation presents solid-state NMR studies of the chain conformation, dynamics and morphology of three adsorbed polymer systems: two random semi-crystalline copolymers, poly(ethylene-co-acrylic acid) (PEA) and poly(propylene-co-acrylic acid) (PPA), and an amorphous homopolymer, poly(n-butyl methacrylate) (PnBMA). Zirconia (ZrO2) was chosen as the substrate for all three polymers since the binding of carboxylic acids to this metal oxide is well understood. The choice of polymers was based on their particular bulk conformational and dynamic properties as well as their common use in polymer coatings. These studies are motivated by the general lack of a microscopic picture of adsorbed polymers, which can be provided by NMR, and the relevance of chain conformation and dynamics to important polymer film properties such as adhesion.First the chain conformation and surface binding of adsorbed PEA as a function of acrylic acid content are characterized by 13C cross polarization - magic angle spinning (CP-MAS), 2D 1H- 13C wideline separation (WISE) and 1H spin diffusion NMR experiments and FTIR-PAS (Fourier transform infrared photoacoustic spectroscopy) measurements. The most important finding is that the chain conformation of adsorbed PEA is determined primarily by the sticker group density rather than the surface coverage. The second study of PEA concerns the chain dynamics in the bulk and adsorbed states. Variable temperature NMR experiments provide evidence that ethylene segments of adsorbed PEA form partially folded loops rather than flat extended trains. Finally 129Xe NMR studies, used to probe the morphology of adsorbed PEA, show a bulk-like signal only for the highest loadings.
The second system investigated, PPA, is another semi-crystalline random copolymer which binds to zirconia via carboxylate linkages. The 13 C CP-MAS NMR spectra of adsorbed PPAC unexpectedly show splittings normally associated with chain-chain packing in the crystalline regions of bulk polypropylene (PP). The splittings in the spectra of adsorbed PPAC, which are more resolved than in bulk PPA, are proposed to arise from recrystallization of the PP segments between sticker groups.
Finally the interfacial properties of an amorphous homopolymer, PnBMA were studied using 13C and 129Xe NMR to characterize adsorbed and filled samples. PnBMA binds to zirconia via the partial hydrolysis of the ester side chains. The remaining ester chains of adsorbed PnBMA are found to segregate to the polymer/air interface. Both adsorbed and ZrO 2-filled PnBMA show enhanced local segmental mobility. However, the 129Xe NMR measurements of the filled samples are consistent with restricted motion on a larger length scale which may be due to particle bridging.
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Senning, Eric Nicolas 1978. "Mitochondrial dynamics and optical conformation changes in DsRed as studied by fourier imaging correlation spectroscopy." Thesis, University of Oregon, 2009. http://hdl.handle.net/1794/10337.
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xiii, 114 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number.Novel experiments that probe the dynamics of intracellular species, including the center-of-mass displacements and internal conformational transitions of biological macromolecules, have the potential to reveal the complex biochemical mechanisms operating within the cell. This work presents the implementation and development of Fourier imaging correlation spectroscopy (FICS), a phase-selective approach to fluorescence spectroscopy that measures the collective coordinate fluctuations of fluorescently labeled microscopic particles. In FICS experiments, a spatially modulated optical grating excites a fluorescently labeled sample. Phase-synchronous detection of the fluorescence, with respect to the phase of the exciting optical grating, can be used to monitor the fluctuations of partially averaged spatial coordinates. These data are then analyzed by two-point and four-point time correlation functions to provide a statistically meaningful understanding of the dynamics under observation. FICS represents a unique route to elevate signal levels, while acquiring detailed information about molecular coordinate trajectories. Mitochondria of mammalian cells are known to associate with cytoskeletal proteins, and their motions are affected by the stability of microtubules and microfilaments. Within the cell it is possible to fluorescently label the mitochondria and study its dynamic behavior with FICS. The dynamics of S. cerevisiae yeast mitochondria are characterized at four discrete length scales (ranging from 0.6 - 1.19 μm) and provide detailed information about the influence of specific cytoskeletal elements. Using the microtubule and microfilament destabilizing agents, Nocodazole and Latrunculin A, it is determined that microfilaments are required for normal yeast mitochondrial motion while microtubules have no effect. Experiments with specific actin mutants revealed that actin is responsible for enhanced mobility on length scales greater than 0.6 μm. The versatility of FICS expands when individual molecules are labeled with fluorescent chromophores. In recent experiments on the tetrameric fluorescent protein DsRed, polarization-modulated FICS (PM-FICS) is demonstrated to separate conformational dynamics from molecular translational dynamics. The optical switching pathways of DsRed, a tetrameric complex of fluorescent protein subunits, are examined. An analysis of PM-FICS coordinate trajectories, in terms of 2D spectra and joint probability distributions, provides detailed information about the transition pathways between distinct dipole-coupled DsRed conformations. This dissertation includes co-authored and previously published material.
Committee in charge: Tom Stevens, Chairperson, Chemistry; Andrew Marcus, Advisor, Chemistry; Peter von Hippel, Member, Chemistry; Marina Guenza, Member, Chemistry; John Toner, Outside Member, Physics
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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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Kinose, Yuji. "Fundamental and Applied Studies on Molecular Bottlebrushes with Particular Reference to Side-Chain Conformation and Dynamics." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263685.
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Lott, Geoffrey Adam 1980. "Probing local conformation and dynamics of molecular complexes using phase-selective fluorescence correlation and coherence spectroscopy." Thesis, University of Oregon, 2010. http://hdl.handle.net/1794/10914.
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xv, 177 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number.When two or more fluorescent chromophores are closely spaced in a macromolecular complex, dipolar coupling leads to delocalization of the excited states, forming excitons. The relative transition frequencies and magnitudes are sensitive to conformation, which can then be studied with optical spectroscopy. Non-invasive fluorescence spectroscopy techniques are useful tools for the study of dilute concentrations of such naturally fluorescent or fluorescently labeled biological systems. This dissertation presents two phase-selective fluorescence spectroscopy techniques for the study of dynamical processes in bio-molecular systems across a wide range of timescales. Polarization-modulated Fourier imaging correlation spectroscopy (PM-FICS) is a novel phase-selective fluorescence spectroscopy for simultaneous study of translational and conformational dynamics. We utilize modulated polarization and intensity gratings with phase-sensitive signal collection to monitor the collective fluctuations of an ensemble of fluorescent molecules. The translational and conformational dynamics can be separated and analyzed separately to generate 2D spectral densities and joint probability distributions. We present results of PM-FICS experiments on DsRed, a fluorescent protein complex. Detailed information on thermally driven dipole-coupled optical switching pathways is found, for which we propose a conformation transition mechanism. 2D phase-modulation electronic coherence spectroscopy is a third-order nonlinear spectroscopy that uses collinear pulse geometry and acousto-optic phase modulation to isolate rephasing and nonrephasing contributions to the collected fluorescence signal. We generate 2D spectra, from which we are able to determine relative dipole orientations, and therefore structural conformation, in addition to detailed coupling information. We present results of experiments on magnesium tetraphenylporphyrin dimers in lipid vesicle bilayers. The 2D spectra show clearly resolved diagonal and off-diagonal features, evidence of exciton behavior. The amplitudes of the distinct spectral features change on a femtosecond timescale, revealing information on time-dependent energy transfer dynamics. This dissertation includes co-authored and previously published material.
Committee in charge: Hailin Wang, Chairperson, Physics; Andrew Marcus, Advisor, Chemistry; Stephen Gregory, Member, Physics; Michael Raymer, Member, Physics; Marina Guenza, Outside Member, Chemistry
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Craigo, Kevin Alan. "Ultrafast Spectroscopic Study of Hydration and Conformational Dynamics in Calmodulin." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1311089745.
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Östervall, Jennie. "Conformational Dynamics of Carbohydrates Studied by NMR Spectroscopy and Molecular Simulations." Doctoral thesis, Stockholms universitet, Institutionen för organisk kemi, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1023.
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Carbohydrates play important roles in biological processes. Their function is closely related to their conformation. In this thesis, conformational studies of carbohydrates by NMR spectroscopy and molecular dynamics computer simulations are described. The first two papers discuss the anomalous solubility of β-cyclodextrin compared to other cyclodextrins. Time correlation functions revealed flexibility in all cyclodextrins. Molecular dynamics computer simulations showed that the glycosidic linkages were rather rigid and the flexibility was suggested to be macrocyclic. From spatial distribution functions β-cyclodextrin was found to have greater ability to order the surrounding water than the other cyclodextrins. Paper III deals with some of the difficulties of conformational studies. In Paper IV, a new method, Additative Potential Maximum Entropy, APME, is applied to a disaccharide. Conformational distribution functions are derived from NOEs, J-couplings and residual dipolar couplings and calculated from computer simulations. All distribution functions were found to be in good agreement. In papers V and VI oligosaccharides from human milk are studied. Residual dipolar coupling, J-couplings and cross relaxation rates were measured by NMR spectroscopy and molecular dynamics computer simulations were carried out. Both oligosaccharides showed high flexibility for the β-D-GlcpNAc-(1→3)-β-D-Galp linkage.
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Bittracher, Andreas [Verfasser], Oliver [Akademischer Betreuer] [Gutachter] Junge, and Carsten [Gutachter] Hartmann. "The generating structure of spatial conformation dynamics / Andreas Bittracher. Betreuer: Oliver Junge. Gutachter: Oliver Junge ; Carsten Hartmann." München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/1108766943/34.
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Bittracher, Andreas Verfasser], Oliver [Akademischer Betreuer] [Junge, and Carsten [Gutachter] Hartmann. "The generating structure of spatial conformation dynamics / Andreas Bittracher. Betreuer: Oliver Junge. Gutachter: Oliver Junge ; Carsten Hartmann." München : Universitätsbibliothek der TU München, 2016. http://nbn-resolving.de/urn:nbn:de:bvb:91-diss-20160721-1302854-1-0.
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Garton, Kelly A. "31P NMR of Backbone Conformation and Dynamics in DNA at Cre Binding Site in Terms of Sequence Context." Scholarship @ Claremont, 2012. http://scholarship.claremont.edu/scripps_theses/100.
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The Cre sequence (ACGT) is a site responsible for the binding of specific transcription factors that determine the activation of genes. Due to its major role in gene transcription, it has become a subject of immense research. The binding of transcription factors to the Cre binding site has been determined to be dependent on DNA conformation. In this study, the effects of flanking sequence around the Cre binding site on the conformation and the dynamics of DNA were investigated. The Cre binding site was studied in its native form with differing flanking sequences to determine the BI/BII profile (conformation) and the magnitude of the energy transition barrier (dynamics) between the BI and BII conformations of each phosphate step of the following three dodecamer sequences: CreACAG, CreGGAG, and CreTATA. In order to obtain the BI/BII profile of each phosphate step, 2D 31P-NMR NOESY and HSQC experiments at various temperatures were utilized. Based of the basic principles of kinetics, the lower the energy barrier between the two conformations, the easier the transition between the BI and BII conformation. Therefore, it was hypothesized that low and high %BII character lead to a large energy barrier (high ∆G‡ values), whereas average %BII character leads to a small energy barrier (low ∆G‡ values). The results of the 2D 31P-NMR experiments of the three dodecamer sequences confirmed this relationship between the %BII character and the magnitude of the energy barrier (∆G‡). However, further conformation and dynamics studies must be conducted to further understand the correlation.
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Klimm, Martina [Verfasser]. "New Strategies in Conformation Dynamics : Investigation of the µ-opioid receptor in healthy and inflamed tissue / Martina Klimm." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1176709100/34.
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Herold, Christoph. "Diffusion and Conformational Dynamics of Semiflexible Macromolecules and Supramolecular Assemblies on Lipid Membranes." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-99296.
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Understanding the interaction of polyelectrolytes with oppositely charged lipid membranes is an important issue of soft matter physics, which provides an insight into mechanisms of interactions between biological macromolecules and cell membranes. Despite the fact that many (bio)macromolecules and filamentous supramolecular assemblies show semiflexible behavior, prior to this work very little was known about the conformational dynamics and Brownian motion of semiflexible particles attached to freestanding lipid membranes. In order to address these issues, diffusion and conformational dynamics of semiflexible DNA molecules and filamentous fd-virus particles electrostatically adsorbed to cationic freestanding lipid membranes were studied on the single particle level by means of optical wide-field fluorescence microscopy. Supergiant unilamellar vesicles (SGUVs) with diameters larger than 100 m represent a perfect model of a freestanding membrane. In this work, a method was developed that enabled the reliable and efficient electroformation of cationic SGUVs on ITO-coated coverslips. The utilization of SGUVs as model freestanding lipid bilayers allowed for determination of the previously unknown surface viscosity of DOPC/DOTAP membranes. In particular, the analysis of the translational diffusion coefficients of small (10, 20, 50 nm) membrane-attached anionic polystyrene beads has shown that the surface viscosity of DOPC/DOTAP membranes with CDOTAP = 1–7 mol% is independent of the DOTAP concentration and equals η = (5.9 ± 0.2) × 10−10 Pa s m.
The fluorescence video-microscopy investigation of single DNA molecules attached to cationic SGUVs revealed a previously unreported conformational transition of a membrane-bound DNA molecule from a 2D random coil, the original conformation in which DNA attaches to the membrane, to a compact globule. This membrane-mediated DNA condensation is favored at high cationic lipid concentrations in the membrane and long DNA contour lengths. The DNA compaction rate in the coil–globule transition is 124 ± 46 kbp/s, and the resulting DNA globule sizes were found to be 250–350 nm at DOPC membranes containing 1 mol% DOTAP and 130–200 nm for 7 mol% DOTAP, indicating a stronger compaction for higher charge densities in the membrane. Additional experiments with freestanding cationic membranes in the gel state and supported cationic lipid membranes with gel–fluid coexistence suggest that the DNA collapse on a freestanding fluid cationic membrane may be initiated by a local lipid segregation in the membrane and is accompanied by local membrane deformations, which eventually stabilize the compact DNA globule.
Furthermore, in this work single molecule studies of random-coil DNA molecules and filamentous fd-virus particles on a freestanding cationic lipid bilayer with a low charge density were carried out. The experiments revealed that these particles can be described as semiflexible chains in 2D. Taken together, DNA molecules and fd-virus particles cover a broad range of the ratio of contour length and persistence length from 0.4 to 82. The results of this work demonstrate that the mobility of such membrane-attached semiflexible particles is strongly affected by hydrodynamics in the lipid membrane and the surrounding bulk fluid, and can in essence be described using a hydrodynamics-based theory for a disk-shaped solid membrane inclusion with a characteristic size approximately equal to the radii of gyration of the particles.
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Curuksu, Jeremy. "Conformational sampling by molecular mechanics and dynamics simulations applied to the flexibility of Nucleic acid." Paris 7, 2009. http://www.theses.fr/2009PA077013.
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Les thématiques adressées dans ma Thèse de Doctorat sont d'une part la flexibilité conformationelle des Acides Nucléiques étudiée par simulations en Dynamique Moléculaire. D'autre part, mes travaux de Thèse adressent deux problèmes principaux rencontrés lors de la pratique des simulations en dynamique moléculaire, à savoir l'échantillonnage limité et le champ de force spécifique utilisé. Trois issues scientifiques à propos de la flexibilité des molécules d'ADN et d'ARN font l'objet de trois chapitres distincts. Premièrement la possibilité d'une dynamique spontanée formant un coude flexible dans les motifs d'ARN ribosomales appelés kink-turns. Deuxièmement la formation spontanée d'un motif coudé très local dans les molécules d'ADN fortement courbées (« kink » entre deux paires de bases). Troisièmement un équilibre entre plusieurs sous états meta-stables dans les angles dièdres du squelette phosphodiester des molécules d'ADN endommagées, dans le cas présent un site abasique (base qui n'a pas de partenaire dans la double hélice d'ADN). Sur le niveau méthodologique nous avons implémenté une coordonnée de réaction spécifique pour chaque projet utilisant la méthode d'Echantillonnage Parapluie (Umbrella Sampling), et développé une nouvelle méthode d'échantillonnage dans le domaine des techniques dites en échange de réplicas (Replica Exchange). Finalement nous montrons qu'en combinant ces deux approches (donc « échantillonnage parapluie en échange de réplicas ») il en résulte un échantillonnage plus efficace et plus précis. Nos résultats permettent d'avoir une meilleure idée sur les coûts d'énergie libre impliqués dans le repliement et la courbure de divers motifs d'acide nucléique, en particulier les kinks dans l'ADNMy PhD dissertation deals with the application of atomic-scale computer simulation (Molecular Dynamics) on different aspects of the conformational flexibility of Nucleic Acids. I have used diverse statistical and computational methods such as Umbrella Sampling and Replica Exchange to extract entropic properties, e. G. Free energy, characterising (i) the bending of DNA on short length-scale, (ii) the folding of recently discovered RNA ribosomal motifs (the kink-tum motif) and (iii) backbone dihedral conformations accessible to damaged DNA. One achievement is the reproduction of the experimental curve for the probability of very high bend angles observed for short fragment of DMA which demonstrates a non linear (softer) bending flexibility of DMA. Indeed the results of my thesis predict that DMA kinks (local defects unstacking neighbour basepairs) occur in vivo and some of them induce a 90°-turn in the hélix. They are associated with a systematic decrease of the local DMA stiffness constant (half an order of magnitude) which was quite unexpected. DNA bending up to 150° on the 5 nm length scale requires on average 12 kcal/mol. It is slightly less expensive, -10 kcal/mol when a run of consecutive adenines is present. Methodological development of Hamiltonian replica exchange sampling techniques enables to characterize several competing DNA backbone conformations accessible to damaged DNA (an abasic site). More generally the PhD thesis presents the development of new methods to tackle the accurate sampling of particular nucleic acid helical propensities, and this is closed with a brief section on an original effort to create a self-learning approach in the context of replica exchange sampling with molecular dynamics
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Bouakil, Mathilde. "Étude de la conformation et de la dynamique conformationnelle de molécules biologiques en phase gazeuse." Thesis, Lyon, 2020. http://www.theses.fr/2020LYSE1145.
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Les protéines sont des molécules dont la structure est liée à leur fonction dans les organismes vivant. Cette thèse porte sur la caractérisation de ces structures et de leur dynamique et s'inscrit dans le développement de l'analyse par spectrométrie de masse en biologie structurale. La spectrométrie de masse couplée à des techniques de spectroscopie optique résolue en temps permet de mettre en lumière les mécanismes d'absorption, de relaxation et de transfert de charges photo-induits impliqués dans la dynamique conformationnelle et électronique de ces molécules biologiques. Ces approches expérimentales avec la combinaison de techniques de biologie moléculaire (expression, gel électrophorèse, dichroïsme circulaire, etc.) sont présentées en début de manuscrit. C'est par l'étude de l'activation photo-induite de chromophores utilisés pour l'analyse de la structure de protéines qu'a commencé ce travail de thèse. Les mécanismes d'absorption de photons et de relaxation non radiative de chromophores greffés sur des peptides ont été sondés. Nous avons ensuite sondé les mécanismes de transferts de charges photo-induits au sein de petits peptides afin de comprendre l'influence de la taille de ces systèmes et de la composition en acides aminés sur la dynamique conformationnelle de ces peptides. Ceci a nécessité le montage d'un dispositif pompe-sonde pour l'étude de la dynamique de transfert de charge. Enfin nous nous sommes intéressés à un processus de changement de conformation du peptide PUMA, présent dans les organismes de mammifères et impliqué dans la régulation de l'apoptose, en utilisant la spectrométrie de mobilité ionique comme sonde de conformation et de dynamique structuraleProtein functions in living organism are governed by their 3D structure. This thesis focuses on the characterization of protein conformation and conformational dynamics by means of mass spectrometry, and participates to the development of tools for structural biology. Mass spectrometry coupled to time resolved optical spectroscopy can set light on mechanisms associated with conformational dynamics: photon absorption, electronic relaxation, photo-induced charge transfer, etc. Experimental approaches combining mass spectrometry, optics and molecular biology (protein expression, gel electrophoresis, circular dichroism, etc.) will be presented in the first section of this manuscript. This thesis work was initiated by the study of the photo-induced activation of the chromophores which were used, at ILM, for action-FRET and more generally for the exploration of the proteins structure. The mechanisms of photon absorption and non-radiative relaxation were studied for chromophores grafted on multiple peptides. We then probed the photo-induced intramolecular charge transfer and associated conformational dynamics in series of small peptides in order to understand the influence of the system size and composition on its structural dynamics. The latter experiment required the implementation of a two-color pump-probe setup. Finally, we used ion mobility spectrometry to probe and investigate the conformational space and dynamics of the PUMA peptide, ubiquitous in mammalian organisms and associated to the regulation of apoptosis
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Reis, Renata Almeida Garcia. "Estudo dinâmico conformacional da proteína calgranulina C (S100A12) mediante interação com íons e receptor RAGE." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/60/60136/tde-03072012-163222/.
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Calgranulina C (S100A12) é membro da família das proteínas S100 \"EF-hands\" que complexam cálcio. A S100A12 humana é expressa predominantemente por granulócitos e é superexpressa em compartimentos inflamatórios. Níveis séricos elevados de S100A12 são encontrados em pacientes acometidos por distúrbios inflamatórios, neurodegenerativos, metabólicos e neoplasias. A S100A12 intracelular existe como um homodímero anti-paralelo. Cada monômero é composto por um \"EF-hand\" clássico, C-terminal (HI - LI - HII), e um \"EF-hand\" N-terminal, o pseudo \"EF-hand\" (HIII - LIII - HIV). Os \"motifs\" são conectados pela região do \"hinge\" (LII). A Calgranulina C também liga íons zinco e cobre em uma região formada pelas duas subunidades do dímero. Mudanças nas concentrações citosólicas de íons regulam uma grande variedade de processos celulares, e as proteínas que complexam íons são moléculas importantes na transdução do sinal, diferenciação e controle do ciclo celular. O mecanismo pelo qual a Calgranulina C modula o curso do processo inflamatório está relacionado à interação com o receptor para produtos finais de glicosilação (RAGE). Para obter detalhes sobre os mecanismos envolvidos nas etapas de sinalização celular das quais a S100A12 participa, nosso objetivo foi qualificar e quantificar a atividade conformacional dos domínios da S100A12 induzida por variações de parâmetros termodinâmicos intensivos, como mudanças nas concentrações de íons. Além disso, nós investigamos os detalhes da interação entre S100A12 e RAGE para elucidar a região do receptor com a qual a S100A12 interage e quais são os resíduos envolvidos nesta interação. Para os estudos da influência da presença de íons na dinâmica conformacional da S100A12, simulações de dinâmica molecular foram realizadas usando o pacote de simulação GROMACS com o campo de força OPLS-AA, no \"ensemble\" NVT. As estruturas iniciais usadas foram as estruturas cristalográficas da S100A12 (PDB ID: 2WCE e 1E8A). Estas foram submetidas a diferentes concentrações de cloreto de sódio, cálcio e zinco em sistemas separados e solvatados com o modelo de água \"SPC\". Nossos resultados sugerem que em baixas concentrações de Ca2+, o LI permanece ocupado pelo Na+. No período entre ondas de Ca2+, este íon tem acesso à proteína exclusivamente pelo LIII (no EF-2). A medida em que há presença de Zn2+, esse contribui para a saída do Na+ do LI, evento que envolve a participação do resíduo Asp25, permitindo que o LI se abra e descomplexe o Na+. Além disso, devido a alta deformabilidade estrutural, a HIII é muito influenciada pelos íons Na+ e Ca2+, sendo que em determinadas concentrações, ambos levam a perda parcial desta hélice e da HIIa (\"Hinge-Region\") e ao aumento da flexibilidade desta região, embora apenas o Ca2+ seja capaz de se complexar, via HIII, a região próxima ao LIII. Com relação aos estudos com o RAGE, foram realizados estudos de \"docking\" molecular e simulações de SMD (\"Steered Molecular Dynamic\"). A análise dos nossos resultados, sugere que a interação da S100A12 com o RAGE ocorre tanto no domínio V, quanto no domínio C1 do RAGE e depende da região de conexão entre estes domínios. Também, observamos que estados oligoméricos maiores, por exemplo, hexâmeros de S100A12 (PDB ID: 1GQM), têm possibilidades maiores de interação com RAGE e que nestes casos, as regiões relevante da interação envolvem, de acordo com nossos resultados, porções N e C-terminal da HI e C-terminal da HIV da S100A12.Calgranulin C (S100A12) is a member of the S100 family of EF-hand calcium-binding proteins. Human S100A12 is predominantly expressed by granulocytes and is markedly overexpressed in inflammatory compartments. Elevated serum levels of S100A12 are found in patients suffering from various inflammatory, neurodegenerative, metabolic, and neoplasic disorders. Intracellular S100A12 exists as an anti-parallel homodimer. Each monomer is composed of a C-terminal, classic EF-hand (HI - LI - HII), an N-terminal, pseudo EF-hand (HIII - LIII - HIV). The motifs are linked by the hinge-region. Calgranulin C also binds zinc and copper ions in a site formed by both subunits of dimer. Changes in cytosolic ions concentrations regulate a wide variety of cellular process, and ions-binding proteins are the key molecules in signal transduction, differentiation, and cell cycle control. The mechanism by which calgranulin C modulates the course of inflammatory process is related to its interaction with the receptor for advanced glycated products (RAGE). In order to obtain details about the mechanism involved in cell signaling steps in which S100A12 participates, our goal was to qualify and quantify the activity conformational of S100A12 domains, induced by variations of intensive thermodynamic parameters, as changes in the concentration of ions. Furthermore we investigated the details of the interaction between S100A12 and RAGE in order to elucidate the region of the receptor which interacts with S100A12 and what are the residues involved in this interaction. In order to access the influence of the presence of ions over the conformational dynamics of S100A12, molecular dynamics simulations were performed using the GROMACS suite with the OPLS-AA force field and NVT ensemble. The initial structures used were experimentally determined by X-ray crystallography (PDB ID: 2WCE and 1E8A). They were separately submitted to different concentrations of sodium, calcium and zinc chloride and solvated with the SPC water model. Our results suggest that at low concentrations of Ca²?, LI remains occupied by Na?. During calcium-waves, it can reach the protein exclusively through LIII (in EF-2). As the Zn²? concentration rises, it contributes to the Na? unbinding from LI, an event that involves the residue ASP-25, which allows LI to open and the Na? to unbind. Furthermore, because of its high structural deformability, HIII is strongly influenced by both Na? and Ca²? ions which, in certain concentrations, leads to partial loss of this helix and of HIIa (Hinge-Region) and increases in the flexibility of this region, although only Ca²? is able to bind, through HIII, to the region near LIII. Regarding the RAGE studies, molecular docking essays and SMD (Steered Molecular Dynamics) simulations were performed. Our data analysis suggests that the interaction between S100A12 and RAGE takes place through both V and C1 RAGE domains and depends upon the interdomain region. Additionally, we observed that higher oligomeric states, e.g. S100A12 hexamers (PDB ID: 1GQM), have more interaction possibilites with RAGE and that, according to our results, in this case the interacting region of S100A12 comprises the N- and C-terminal portions of HI and Cterminal of HIV.
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Krause, Stefan, Pedro F. Aramendia, Daniela Täuber, and Borczyskowski Christian von. "Freezing single molecule dynamics on interfaces and in polymers." Universitätsbibliothek Chemnitz, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:ch1-qucosa-122254.
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Heterogeneous line broadening and spectral diffusion of the fluorescence emission spectra of perylene diimide molecules have been investigated by means of time dependent single molecule spectroscopy. The influence of temperature and environment has been studied and reveals strong correlation to spectral diffusion processes. We followed the freezing of the molecular mobility of quasi free molecules on the surface upon temperature lowering and by embedding into a poly(methyl methacrylate) (PMMA) polymer. Thereby changes of optical transition energies as a result of both intramolecular changes of conformation and external induced dynamics by the surrounding polymer matrix could be observed. Simulations of spectral fluctuations within a two-level system (TLS) model showed good agreement with the experimental findings.
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Bougueroua, Sana. "Caractérisation de structures explorées dans les simulations de dynamique moléculaire." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLV099/document.
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L’objectif de cette thèse est d’analyser et prédire les conformations d’un système moléculaire en combinant la théorie des graphes et la chimie computationnelle.Dans le cadre des simulations de dynamique moléculaire, une molécule peut avoir une ou plusieurs conformations au cours du temps. Dans les trajectoires de simulation de dynamique moléculaire, on peut avoir des trajectoires n’explorant qu’une seule conformation ou des trajectoires explorant plusieurs conformations, donc plusieurs transitions entre conformations sont observées. L’exploration de ces conformations dépend du temps de la simulation et de l'énergie (température) fixée dans le système. Pour avoir une bonne exploration des conformations d’un système moléculaire, il faut générer et analyser plusieurs trajectoires à différentes énergies. Notre objectif est de proposer un algorithme universel qui permet d’analyser la dynamique conformationnelle de ces trajectoires d’une façon rapide et automatique. Les trajectoires fournissent les positions cartésiennes des atomes du système moléculaire à des intervalles de temps réguliers. Chaque intervalle contenant un ensemble de positions est appelé image. L’algorithme utilise des règles de géométrie (distances, angles, etc.) sur les positions pour trouver les liaisons (liaisons covalentes, liaisons hydrogène et interactions électrostatiques) créées entre les atomes, permettant par la suite d’obtenir le graphe mixte qui modélise une conformation. Nous ne considérons un changement conformationnel que s’il y a un changement dans les liaisons calculées à partir des positions données. L’algorithme permet de donner l’ensemble des conformations explorées sur une ou plusieurs trajectoires, la durée d’exploration de chaque conformation, ainsi que le graphe de transitions qui contient tous les changements conformationnels observés.Les conformations se caractérisent par une énergie appelée énergie potentielle. Cette énergie est représentée par une courbe appelée surface d’énergie potentielle. En chimie théorique et computationnelle, certains s’intéressent à trouver des points particuliers sur cette surface. Il s'agit des minima qui représentent les conformations les plus stables et des maxima ou états de transition qui représentent les points de passage d'une conformation à une autre. En effet, d'une part, la conformation la plus stable est celle de plus basse énergie. D'autres part, pour aller d’une conformation à une autre il faut une énergie supplémentaire, le point maximum représente l'état de transition. Les méthodes développées pour calculer ces points nécessitent une connaissance de l’énergie potentielle ce qui est coûteux en temps et en calculs. Notre objectif est de proposer une méthode alternative en utilisant des mesures ah doc basées sur des propriétés des graphes qu’on a utilisées dans le premier algorithme et sans faire appel à la géométrie ni aux calculs moléculaires. Ces mesures permettent de générer des conformations avec un classement énergétique ainsi de définir le coût énergétique de chaque transition permise. Les conformations possibles avec les transitions représentent respectivement les sommets et les arcs de ce qu’on appelle le “graphe des possibles”. Les hypothèses utilisées dans le modèle proposé est que seules les liaisons hydrogène peuvent changer entre les conformations et que le nombre de liaisons hydrogène présentes dans le système permet de déterminer son coût énergétique.L’algorithme d'analyser des trajectoires a été testé sur trois types de systèmes moléculaires en phase gazeuse de taille et de complexité croissantes. Bien que la complexité théorique de l’algorithme est exponentielle (tests d’isomorphisme) les résultats ont montré que l’algorithme est rapide (quelques secondes). De plus, cet algorithme peut être facilement adapté et appliqué à d’autres systèmes. Pour la prédiction conformationnelle, le modèle proposé a été testé sur des peptides isolésThis PhD is part of transdisciplinary works, combining graph theory and computational chemistry.In molecular dynamics simulations, a molecular system can adopt different conformations over time. Along a trajectory, one conformation or more can thus be explored. This depends on the simulation time and energy within the system. To get a good exploration of the molecular conformations, one must generate and analyse several trajectories (this can amount to thousands of trajectories). Our objective is to propose an automatic method that provides rapid and efficient analysis of the conformational dynamics explored over these trajectories. The trajectories of interest here are in cartesian coordinates of the atoms that constitute the molecular system, recorded at regular time intervals (time-steps). Each interval containing a set of positions is called a snapshot. At each snapshot, our developed algorithm uses geometric rules (distances, angles, etc.) to compute bonds (covalent bonds, hydrogen bonds and any other kind of intermolecular criterium) formed between atoms in order to get the mixed graph modelling one given conformation. Within our current definitions, a conformational change is characterized by either a change in the hydrogen bonds or in the covalent bonds. One choice or the other depends on the underlying physics and chemistry of interest. The proposed algorithm provides all conformations explored along one or several trajectories, the period of time for the existence of each one of these conformations, and also provides the graph of transitions that shows all conformational changes that have been observed during the trajectories. A user-friendly interface has been developed, that can de distributed freely.Our proposed algorithm for analysing the trajectories of molecular dynamics simulations has been tested on three kinds of gas phase molecular systems (peptides, ionic clusters). This model can be easily adapted and applied to any other molecular systems as well as to condensed matter systems, with little effort. Although the theoretical complexity of the algorithm is exponential (isomorphism tests), results have shown that the algorithm is rapid.We have also worked on computationally low cost graph methods that can be applied in order to pre-characterize specific conformations/points on a potential energy surface (it describes the energy of a system in terms of positions of the atoms). These points are the minima on the surface, representing the most stable conformations of a molecular system, and the maxima on that surface, representing transition states between two conformers. Our developed methods and algorithms aim at getting these specific points, without the prerequisite knowledge/calculation of the potential energy surface by quantum chemistry methods (or even by classical representations). By avoiding an explicit calculation of the potential energy surface by quantum chemistry methods, one saves computational time and effort. We have proposed an alternative method using ad doc measures based on properties of the graphs (already used in the first part of the PhD), without any knowledge of energy and/or molecular calculations. These measures allow getting the possible conformations with a realistic energy classification, as well as transition states, at very low computational cost. The algorithm has been tested on gas phase peptides
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Murzycki, Jennifer E. "Probing Protein Dynamics Through Mutational and Computational Studies of HIV-1 Protease: A Dissertation." eScholarship@UMMS, 2006. https://escholarship.umassmed.edu/gsbs_diss/166.
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How proteins undergo conformational changes to bind a ligand is one of the most fundamental questions of protein biology. MD simulations provide a useful computational tool for studying the theoretical movements of protein in solution on nanosecond timescales. The results of these simulations can be used to guide experimental design. By correlating the theoretical models with the results of experimental studies, we can obtain a significant amount of information about protein dynamics. This study represents the application of both computational and traditional experimental techniques to study protein dynamics in HIV-1 protease. The results provide a novel mechanism for the conformational changes in proteins and address the role of residues outside the active site in protein dynamics. Additionally, these results are applied to the complex role of non-active site mutations in the development of drug resistance.
Chapter II examines an invariant Thr80 at the apex of the P1 loop of HIV-1, HIV-2, and simian immunodeficiency virus protease. Sequence variability associated with human immunodeficiency virus type 1 (HIV-1) is useful for inferring structural and/or functional constraints at specific residues within the viral protease. Positions that are invariant even in the presence of drug selection define critically important residues for protease function. Three protease variants (T80V, T80N, and T80S) were examined for changes in structure, dynamics, enzymatic activity, affinity for protease inhibitors, and viral infectivity. While all three variants were structurally similar to the wild type, only T80S was functionally similar. T80V significantly decreased the ability of the enzyme to cleave a peptide substrate but maintained infectivity, while T80N abolished both activity and viral infectivity. Additionally, T80N decreased the conformational flexibility of the flap region, as observed by simulations of molecular dynamics. Taken together, these data indicate that HIV-1 protease functions best when residue 80 is a small polar residue and that mutations to other amino acids significantly impair enzyme function, possibly by affecting the flexibility of the flap domain.
Chapter III focuses on residues within the hydrophobic core of each monomer in HIV-1 protease. Many hydrophobic residues located in the core of this dimeric enzyme frequently mutate in patients undergoing protease inhibitor therapy. The mechanism by which these mutations aid the development of drug resistance is not well understood. Using MD simulations, this study suggests that the hydrophobic residues outside the active site facilitate the conformational change that occurs in HIV-1 protease upon binding substrates and inhibitors. In these simulations, the core of each monomer significantly rearranges to assist in the expansion of the active site as hydrophobic core residues slide by each other, exchanging one hydrophobic contact for another. Such hydrophobic sliding may represent a general mechanism by which proteins undergo conformational changes. Mutation of these hydrophobic core residues would alter the packing of the hydrophobic core. Thus, these residues could facilitate drug resistance in HIV-1 protease by altering dynamic properties of HIV-1 protease preferentially affecting the relative affinity for inhibitors versus substrates.
Chapter IV concentrates on a residue in the flap region, Ile54, which is significantly correlated with the development of drug resistance. A series of patient sequences containing the mutation I54A were evaluated for the most frequently occurring co-mutations. I54A was found to occur with mutations that were previously correlated with I54V mutations, including L10I, G48V, and V82A. Based on the results of this evaluation, the binding properties of five variant proteases were investigated: MDI54V, MDRI54A, I54V, I54A, and G48V. MDRI54V and MDRI54Aeach contained the mutations L10I, G48V, and V82A, and either I54V or I54A, respectively. The other variants contained only the mutation indicated. Mutations at Ile54 were able to significantly impact the thermodynamics of binding to saquinavir, amprenavir, and the recently approved darunavir. The magnitude of this impact depended on the presence or absence of other drug resistance mutations, including another mutation in the flap region, G48V. Therefore, while residues 48 and 54 are not in contact with each other, mutations at both sites had a cooperative effect that varies between inhibitors.
The results demonstrate that residues outside the active site of HIV-1 protease are clearly important to enzyme function, possibly through their role in the dynamic properties of protease. Mutations outside the active site of protease that are known to cause drug resistance could alter the conformational flexibility of protease. While the role of protein dynamics in molecular recognition is still not fully understood, the results of this study indicate that altering the dynamic properties of a protein affects its ability to recognize ligands. Therefore, to design better inhibitors we will have to develop a more thorough understanding of protein dynamics.
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Omowunmi, Sunday Chima. "Modelling the nonlinear dynamics of polymer solutions in complex flows." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/modelling-the-nonlinear-dynamics-of-polymer-solutions-in-complex-flows(3230a688-0ea4-4620-bda1-396346feb645).html.
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The flow of polymer solutions in the high Elasticity number, El, regime in complex geometries may lead to strong viscoelastic behaviour and eventually become unstable as the Weissenberg number, Wi, is increased beyond a critical level. So far, the success of numerical simulations in predicting the highly non-linear behaviour of polymer solutions in complex flows has been limited. In this thesis, selected constitutive models are evaluated under the high El flow regime in the cross-slot and contraction benchmark flows using a numerical technique based on the finite volume method. The numerical technique is implemented within the OpenFOAM framework and thoroughly validated in the benchmark flow. A modification to the FENE dumbbell model based on the non-affine deformation of polymer solutions is proposed, which enabled the prediction of some non-linear material functions and also enhanced numerical stability, allowing a higher Wi to be attained. Asymmetric flow instability in the cross-slot flow has been studied. Time-dependent stability diagrams were constructed based on Wi and the strain, ε, both of which govern the stretching of a polymer chain. In the contraction flow, elastic instability is simulated for the first time in this geometry. Substantial time-dependent asymmetric flow patterns were predicted as seen in experiments. The effect of the contraction ratio is investigated through a stability diagram. Three-dimensional finite element simulations were also carried out to study the effect of the aspect ratio in the contraction flow of a Phan-Thien-Tanner fluid. The simulations suggest that a lip vortex mechanism is a signature for the onset of strong viscoelastic behaviour.
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Webber, Benjamin Charles. "Investigation of the Structure and Dynamics of Regioisomeric Eu³⁺ and Gd³⁺ Chelates of NB-DOTMA: Implications for MRI Contrast Agent Design." PDXScholar, 2013. https://pdxscholar.library.pdx.edu/open_access_etds/1498.
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The detection of disease and abnormal pathology by magnetic resonance imaging (MRI) has been aided significantly by the use of gadolinium (Gd3+)-based contrast agents (CAs) over the past three decades. MRI and MRI CAs play a critical role in diagnosing tumors and diseases of the central nervous system. The agents used clinically have been shown to safely increase MRI contrast despite the toxicity of Gd3+, owing to the high kinetic and thermodynamic stability of these chelates. However, current CAs enhance contrast at a small fraction of what is theoretically possible. This leads to the necessity of introducing high CA doses in practice in order to afford sufficient contrast. Lanthanide (Ln3+) chelates based on 1,4,7,10–tetraazacyclododecane–1,4,7,10–tetraacetate (DOTA) have been shown to be particularly stable and effective. Chelates of DOTA exist in two interconverting coordination geometries which have varying water exchange rates. Researchers have envisioned a way to increase the per-dose efficacy both by control of the Gd3+–inner–sphere water exchange rate and via binding specificity (i.e. to tumors). The efficacy gains using these approaches have thus far been modest.
A thorough structural characterization of europium (Eu3+) chelates of a DOTA-derivative which cannot undergo conformational exchange was carried out. These studies show that a single enantiomer of the ligand (S)–2–(4-nitrobenzyl)–1,4,7,10–tetraazacyclododecane–1,4,7,10–tetra(α–methyl)acetate (NB–DOTMA) can yield chelates which are both diastereoisomeric (previously reported) and regioisomeric (not previously speculated). Molecular mechanics simulations generated from the characterization data indicate that the nitrobenzyl (NB) substituent is oriented in different directions for the two possible regioisomers. The NB group can be chemically converted to confer macromolecular binding capability, and the orientation of the NB substituent may have a significant impact on the binding and/or relaxation behavior of a prototypical CA.
The nuclear magnetic resonance (NMR) spectra of Eu–NB–DOTMA at various temperatures were compared. Unexpectedly, the chelates showed time-averaged structures which differ with a change in water exchange rate — the faster the rate, the greater the deviation from the expected structure. Consideration of the structures of Ln3+ chelates without accounting for their dynamic behavior does not yield an accurate value for the time-averaged hydration state. These observations suggest the "optimal" water exchange rate calculated using Solomon-Bloembergen-Morgan (SBM) theory may not lead to the highest-efficacy CAs. Binding and relaxometric studies of macromolecule-targeting derivatives of Gd–NB–DOTMA both by the author and in another lab showed that the coordination isomer with the slower water exchange rate should lead to more effective contrast, in direct opposition to the prevailing view of water exchange in the MRI community. Preliminary data do not indicate that regioisomeric chelates have significantly different relaxivity or macromolecular binding behavior.
The ratios between regioisomeric Ln–NB–DOTMA chelates formed were shown to be dependent on the concentration and pH of the chelation reaction, but conditions were not found which led to the production of a single regioisomer. Attempts to carry out an efficient synthesis of a Ln3+ chelate with no potential for regioisomerism were unsuccessful.
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Murciano, Brice. "Dynamique conformationnelle chez les protéines d'adhésion de Babesia : mythe ou réalité ?" Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON13510/document.
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L'une des infections parasitaires les plus courantes chez les animaux à travers le monde est la babésiose ou piroplasmose. Causée par le développement intraérythrocytaire d'un parasite du genre Babesia, elle présente de nombreux signes cliniques semblables à ceux du paludisme. Ce parasite, du phylum des Apicomplexes, est transmis via le vecteur tique et effectue son cycle de reproduction dans les cellules rouges du sang de l'hôte vertébré. En Europe B. divergens et B. canis sont les espèces majoritairement responsables respectivement de la babésiose bovine et la babésiose canine. Dans une stratégie de recherche vaccinale, l'étude de protéines parasitaires en contact avec la circulation sanguine est primordiale pour comprendre les interactions hôte-parasite et identifier des candidats vaccins à haut potentiel. Les protéines à ancrage GPI (glycosylphosphatidylinositol) font partie de ces protéines. La première protéine à ancrage GPI décrite chez B. divergens est Bd37.1. Elle induit une protection totale contre une infection à B. divergens à la condition qu'une séquence hydrophobe soit ajoutée en C-terminale. La résolution de la structure RMN de cette protéine a permis de mettre en évidence un probable mécanisme de changement conformationnel en fonction du pH. La structure composée de 3 sous domaines montre que celle-ci n'est maintenue que par des ponts salins qui peuvent se rompre en milieu acide. Or l'environnement membranaire dans lequel évolue Bd37.1 ancrée à la surface du parasite et/ou à l'approche du globule rouge lors de l'invasion est acide. Cette dynamique conformationnelle de la protéine Δ-Bd37, liée à l'environnement membranaire, pourrait être à l'origine du mécanisme qui confère une immunité en fonction de la présence ou non de la séquence hydrophobe en C-terminale de Bd37.1. Nous avons cherché à estimer les implications d'une telle dynamique dans les interactions hôtes-parasites à travers l'étude structurale de 2 protéines parasitaires (Bd37.1 et Bc28.1). Dans le premier cas nous étudions la dynamique conformationnelle de la protéine d'adhésion Bd37.1. Nous avons exploré les différentes conformations que pourrait adopter la protéine Bd37.1 par une approche de biophysique et nous avons stabilisé ces différentes conformations en solution par le biais de mutations pour les étudier. Parmi ces mutants, le mutant EDK-Δ-Bd37 dont les ponts salins ont été rompus montre des caractéristiques différentes de Δ-Bd37. Les données enregistrées sur ce mutant nous ont amené à résoudre sa structure et à tester son pouvoir vaccinant. Dans une seconde partie, nous caractérisons biochimiquement et fonctionnellement une autre protéine Bc28.1, l'orthologue de Bd37.1. chez B. canis, accompagnée de la résolution de sa structure. Nous montrons que Bc28.1 est une protéine d'adhésion localisée à la surface du parasite et nous comparons les structures de Bd37.1 et Bc28.1. Ces deux structures sont finalement très différentes tandis que localisation et fonction sont similairesOne of the most common parasitic infections in animals worldwide is babesiosis or piroplasmosis. Caused by the intraerythrocytic development of Babesia parasite, it has many clinical signs similar to those of malaria. This parasite of the phylum Apicomplexa, is transmitted via the tick vector and performs its reproductive cycle in red blood cells of the vertebrate host. B. In Europe divergens and B. canis species are mainly responsible respectively for bovine babesiosis and canine babesiosis. A strategy of vaccine research, the study of parasite proteins in contact with the bloodstream is essential for understanding host-parasite interactions and identify vaccine candidates with high potential. Anchored protein GPI (glycosylphosphatidylinositol) are part of these proteins. The first protein GPI anchors described in B. divergens is Bd37.1. It induces complete protection against infection with B. divergens provided a hydrophobic sequence is added at the C-terminus. Resolution NMR structure of this protein has highlighted a probable mechanism of conformational change as a function of pH. The structure consists of three sub areas shows that it is only maintained by salt bridges which can break in acidic medium. However, the environment within which Bd37.1 membrane anchored to the surface of the parasite and / or approach the red blood cell during the invasion is acidic. This conformational dynamics of the protein-Δ Bd37 linked to the membrane environment, could be at the origin of the mechanism that confers immunity depending on the presence or absence of the hydrophobic sequence at the C-terminus of Bd37.1. We sought to assess the implications of such dynamics in host-parasite interactions through structural study of two parasite proteins (Bd37.1 and Bc28.1). In the first case we study the conformational dynamics of the adhesion protein Bd37.1. We explored the different conformations that may be adopted by a protein Bd37.1 biophysical approach and we have stabilized in different conformations in solution through mutations to study. Among these mutants, the mutant Δ-Bd37-EDK including salt bridges were broken shows different characteristics Δ-Bd37. The data on this mutant led us to solve the structure and to test its power vaccinating. In a second part, we characterize biochemically and functionally Bc28.1 another protein, the ortholog Bd37.1. in B. canis, accompanied with the resolution of its structure. We show that Bc28.1 is an adhesion protein localized to the parasite surface and compare the structures and Bd37.1 Bc28.1. These two structures are ultimately very different while location and function are similar
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Galupa, Rafael. "Exploring the structural and functional dynamics of the X-inactivation centre locus during development." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS305.
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La régulation de l’expression génique chez les mammifères dépend de l’organisation tridimensionnelle des chromosomes, en particulier à l’échelle des communications entre les séquences régulatrices et leurs promoteurs cibles. Ainsi, les chromosomes sont organisés en une nouvelle architecture consistant en domaines d’interactions topologiques (TADs, acronyme anglais). Mon projet de thèse avait pour but de caractériser les mécanismes moléculaires impliqués dans cette architecture et leurs importances au cours du développement embryonnaire, pour un locus bien particulier, le Xic (acronyme anglais pour X-inactivation centre). Le Xic contient les éléments régulateurs nécessaires pour initier l’inactivation du chromosome X (ICX), un phénomène épigénétique spécifique du développement des mammifères femelles, rendant l’un des deux chromosomes X inactif du point de vue transcriptionnelle. L’ICX permet d’égaliser l’expression des gènes liés au X entre les sexes chez les mammifères. Le Xic est organisé au moins en deux TADs mais une partie du locus reste encore non identifiée. Je présente ici une analyse fonctionnelle approfondie des différents éléments régulateurs au sein du Xic, comprenant des enhancers, des gènes d’ARNs non codants et des éléments structurels. Après avoir créé une série d’allèles mutés chez la souris et les cellules souches embryonnaires murines, j’ai caractérisé l’impact de ces réarrangements génomiques sur le paysage structurel et transcriptionnel du Xic. J’ai identifié des nouveaux acteurs dans la régulation de ce locus, en particulier des séquences régulatrices conservées chez les mammifères placentaires et des éléments structurels importants pour la formation d’une frontière entre les deux TADs du Xic, importante pour leur séparation et régulation. Je décris aussi la découverte de communication entre ces TADs, ce qui constitue un mécanisme inédit de régulation génique pendant le développement. Ce travail contribue à un nouveau niveau de compréhension des lois qui régissent l’organisation des TADs dans le contexte de la régulation génique chez les mammifèresMammalian gene regulatory landscapes rely on the folding of chromosomes in the recently discovered topologically associating domains (TADs), which ensure appropriate communication between cis-regulatory elements and their target promoters. The aim of my PhD project was to characterise the molecular mechanisms that govern this novel architecture and its functional importance in the context of a critical and developmentally regulated locus, the X-inactivation centre (Xic). The Xic contains the necessary elements to trigger X-chromosome inactivation, an epigenetic phenomenon that occurs during the development of female mammals to transcriptionally silence one of the X-chromosomes and equalise X-linked gene expression between sexes. The Xic is partitioned into at least two TADs, but its full extent is unknown. Here, I present a comprehensive functional analysis of different cis-regulatory elements within the Xic, including enhancer-like regions, long noncoding RNA loci and structural elements. Upon generating a series of mutant alleles in mice and murine embryonic stem cells, I characterised the impact of these genomic rearrangements in the structural and transcriptional landscape of the Xic and identified novel players in the regulation of this locus, including cis-acting elements conserved across placental mammals and structural elements critical for the insulation between the Xic TADs. I also found evidence for communication across TADs at this locus, which provides new insights into how regulatory landscapes can work during development. This study also extends our understanding of the rules governing the organisation of TADs and their chromatin loops in the context of mammalian gene regulation
Nos mamíferos, a regulação da expressão genética depende da organização tridimensional dos cromosomas, em particular ao nível da comunicação regulatória entre promotores e enhancers. A esta escala, descobriu-se recentemente que os cromossomas estão organizados em domínios de interações topológicas (conhecidos como TADs, no acrónimo inglês) que se pensa providenciarem uma base estrutural para as paisagens de regulação transcricional dos genes. O meu projecto de tese teve como objectivo caracterizar os mecanismos moleculares responsáveis por esta arquitectura e a sua importância funcional no contexto de um locus crítico para o desenvolvimento embrionário, o centro de inactivação do cromossoma X (Xic, acrónimo inglês). O Xic contém os elementos genéticos necessários e suficientes para iniciar a inactivação do cromossoma X, um fenómeno epigenético que ocorre durante o desenvolvimento das fêmeas de mamíferos para silenciar um dos cromosomas X e igualar a expressão dos genes do X entre indivíduos XX e XY. O Xic está organizado em pelo menos dois TADs, mas o seu intervalo genético completo permanece desconhecido. Apresento nesta tese uma análise funcional e detalhada de diferentes sequências reguladoras presentes no Xic, incluindo regiões do tipo enhancer, genes de ARNs não codificantes e elementos estruturais. Após a criação de diversos alelos mutantes (deleções, inserções, inversões) em ratinho e em células estaminais embrionárias, através das recentes técnicas de engenharia genética, TALENs e CRISPR/Cas9, caracterizei o impacto destes rearranjos genéticos na paisagem topológica e transcricional do Xic, o que permitiu a identificação de novos actores moleculares na regulação deste locus. Em particular, descobrimos sequências de regulação transcricional altamente conservadas em mamíferos placentários e elementos estruturais importantes para a formação da fronteira entre os dois TADs do Xic. Descrevo também evidência de que há comunicação entre os dois TADs neste locus, o que compromete os modelos actuais do modus operandis dos TADs, e por isso contribui para um novo nível de compreensão dos mecanismos que regulam a expressão genética durante o desenvolvimento
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Hartmann, Brigitte. "Contribution a l'etude du polymorphisme et de la structure dynamique de l'adn-z." Orléans, 1987. http://www.theses.fr/1987ORLE2038.
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La conformation des oligonucleotides (m**(5)dc-dg)::(2), (m**(5)dcdg)::(3) et (br**(5)dc-dg)::(3) peut etre sous forme b et z. Les stabilites thermiques de ces 2 formes sont differentes la fusion de la forme b est monophasique, celle de la forme est biphasique. Une premiere transition a ete observe, refletant un remaniement conformationnel intramoleculaire. Ce remaniement intramoleculaire conduit de la forme z a une double helice gauche dont le caractere de nucleotidique de l'unite repetitive est atteint et ou l'empilement des bases est modifie. L'etude du mecanisme d'echange chimique des protons de la guanine montre que dans tous les tampons utilisees catalysent le transfert en accord avec la theorie de biomoted. Etude comparative des cinetiques d'echange des formes z a permis d'attribuer les 2 protons lents aux protons amino de la cytosine
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Krause, Stefan, Pedro F. Aramendia, Daniela Täuber, and Borczyskowski Christian von. "Freezing single molecule dynamics on interfaces and in polymers." Physical Chemistry Chemical Physics. - 2011,13, S. 1754-1761, 2011. https://monarch.qucosa.de/id/qucosa%3A19944.
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Heterogeneous line broadening and spectral diffusion of the fluorescence emission spectra of perylene diimide molecules have been investigated by means of time dependent single molecule spectroscopy. The influence of temperature and environment has been studied and reveals strong correlation to spectral diffusion processes. We followed the freezing of the molecular mobility of quasi free molecules on the surface upon temperature lowering and by embedding into a poly(methyl methacrylate) (PMMA) polymer. Thereby changes of optical transition energies as a result of both intramolecular changes of conformation and external induced dynamics by the surrounding polymer matrix could be observed. Simulations of spectral fluctuations within a two-level system (TLS) model showed good agreement with the experimental findings.
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Ceres, Nicoletta. "Coarse-grain modeling of proteins : mechanics, dynamics and function." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10030.
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Les protéines sont des molécules flexibles, qui accomplissent une variété de tâches cellulaires à travers des mouvements mécaniques et des changements conformationnels encodés dans leur structure tridimensionnelle. Parmi les approches théoriques qui contribuent à une meilleure compréhension de la relation entre structure, mécanique, dynamique et fonction des protéines, les modèles gros-grains sont un outil très puissant. Ils permettent d’intégrer des informations structurales et dynamiques à un coût computationnel réduit, car le traitement explicite des degrés de liberté moins importants est supprimé. Dans le cadre de cette thèse, des études comparatives rapides de la flexibilité et de la mécanique des protéines ont été menées en se servant du simple modèle gros-grains de Réseau Élastique. La dépendance des résultats de la conformation de départ, ainsi que une liberté dynamique de la chaine principale plutôt limitée, imposée par l’approximation harmonique, nous ont motivé à développer une nouvelle approche, permettant une exploration plus extensive de l’espace conformationnel. Les efforts ont conduit à PaLaCe, modèle gros-grains qui permet des changements majeurs de la structure secondaire, tout en gardant la spécificité de la séquence des acides aminés grâce à une représentation à basse résolution. En utilisant PaLaCe nous avons simulé deux processus impliquant la plasticité protéique: le dépliement du domaine I27 de la protéine musculaire titine et la dynamique à l’équilibre autour de la structure native de deux enzymes homologues adaptées à des températures différentes. Les résultats obtenus concordent avec les données expérimentales et les résultats issus de modèles tout-atom déjà publiés. PaLaCe s’avère donc être un modèle fiable, avec des temps de calcul restreints par rapport aux modèles tout-atome, tout en conservant un bon niveau de détail. Il offre ainsi la possibilité d’effectuer une recherche systématique sur les liens entre mécanique, dynamique et fonction des protéinesProteins are flexible molecules, which accomplish a variety of cellular tasks through mechanical motions and conformational fluctuations encoded in their three-dimensional structure. Amongst the theoretical approaches contributing to a better understanding of the relationship between protein structure, mechanics, dynamics and function, coarse-grain models are a powerful tool. They can be used to integrate structural and dynamic information over broad time and size scales at a low computational cost, achieved by averaging out the less important degrees of freedom. In this work, fast comparative studies of protein flexibility and mechanics have been performed with the simple coarse-grain Elastic Network Model. However, the dependency of the results on the starting conformation, and the rather constrained backbone dynamics imposed by the harmonic approximation, motivated the development of a new approach, for a more extensive exploration of conformational space. These efforts led to the PaLaCe model, designed to allow significant changes in secondary structure, while maintaining residue specificity despite a lower-level resolution. Using PaLaCe, we were able to reproduce two processes involving protein plasticity: the mechanical unfolding of the I27 domain of the giant muscle protein titin and the near-native dynamics of two homologous enzymes adapted to work at different temperatures. Agreement with experimental data and results from published atomistic models demonstrate that PaLaCe is a reliable, sufficiently accurate, but computationally inexpensive approach. It therefore opens the doors for a systematic investigation of the link between protein dynamics/mechanics and function
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Boccongelli, Marina. "Etude expérimentale de la stabilité, sélectivité d'appariement et dynamique d'oligonucléotides DNA-DNA et LNA-DNA." Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210549.
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Le traitement et le diagnostic de maladies d'origine génétique suscite un grand intérêt à l'heure actuelle. De par leur spécificité d'appariement avec les acides nucléiques, les oligonucléotides possèdent un grand potentiel dans ce domaine. Ils se heurtent toutefois à des limitations majeures, dont leur faible stabilité en milieu physiologique et la difficulté qu'ils ont à franchir les membranes biologiques. De nombreuses équipes de recherche s'intéressent, afin de pallier ces limitations, à la conception et à la synthèse d'oligonucléotides chimiquement modifiés. Parmi ceux-ci, les Locked Nucleic Acids (LNA), présentant une modification qui consiste en l'insertion d'un pont −O−CH2− entre l'atome C2' et l'atome C4' du sucre, constituent une famille qui semble posséder les propriétés requises. Ils sont considérés comme des candidats très prometteurs en tant qu’agents thérapeutiques et qu’outils de diagnostic du génome. La caractérisation de la stabilité et de la sélectivité d'appariement entre les LNA et les acides nucléiques naturels est, dans ce contexte, important.Dans ce travail, nous avons étudié la stabilité, la sélectivité d'appariement ainsi que la dynamique de la structure double brin d'un oligonucléotide hybride LNA-DNA, et nous avons comparé ces propriétés à celles d'un oligonucléotide DNA-DNA de même séquence. Ce dernier est constitué de 11 paires de bases formées par l'appariement du brin 5'-GCGTGTGTGCG-3' avec le brin 3'-CGCACACACGC-5'. Dans le cas de l'hybride, les nucléotides du second brin sont tous remplacés par des LNA.
La stabilité a été étudiée expérimentalement par différentes techniques :spectroscopie d'absorption UV, calorimétrie différentielle à balayage, résonance magnétique nucléaire et calorimétrie à titrage isotherme. Ces études montrent que la stabilité du duplexe hybride est plus importante que celle du naturel, et que ce phénomène s'explique par un terme entropique plus favorable pour la formation du duplexe LNA-DNA que pour la formation du duplexe DNA-DNA.
La sélectivité d'appariement a été étudiée en comparant la stabilité des deux oligonucléotides étudiés avec celle d'oligonucléotides présentant un mésappariement dans la séquence. Nos résultats montrent que la sélectivité d'appariement du brin LNA n'est pas significativement différente de celle du brin DNA. Ce résultat ne doit cependant pas être généralisé car nous n'avons testé qu'une position centrale pour le mésappariement.
L'étude de la dynamique de la structure des oligonucléotides a été effectuée par RMN et porte sur la caractérisation de la cinétique de l'ouverture individuelle des paires de bases. Nous observons que la durée de vie de l'état fermé des paires de bases G-C est supérieure dans l'oligonucléotide LNA-DNA, tandis que l'état fermé des paires A-T semble posséder une durée de vie supérieure dans l'oligonucléotide DNA-DNA.
Au cours de ce travail de thèse nous avons pu caractériser les facteurs énergétiques à la base de la stabilité accrue des oligonucléotides chimiquement modifiés de type LNA. Nous avons montré que leur sélectivité d’appariement n’est pas toujours supérieure à celle des oligonucléotides naturels et dépend des séquences impliquées. Enfin, nous avons mis en évidence les différences entre la dynamique de la structure d’un oligonucléotide possédant des LNA et celle d’un duplexe DNA.
Doctorat en Sciences de l'ingénieur
info:eu-repo/semantics/nonPublished
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Ferrari, Marta. "Dynamic conformation : the influence of conformation on equine locomotion." Thesis, Royal Veterinary College (University of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.519518.
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Narwani, Tarun Jairaj. "Dynamics of protein structures and its impact on local structural behaviors." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC160/document.
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Les structures protéiques sont de nature hautement dynamique contrairement à leur représentation dans les structures cristallines. Une composante majeure de la dynamique structurelle est la flexibilité des protéines inhérentes. L'objectif principal de cette thèse est de comprendre le rôle de la dynamique inhérente dans les structures protéiques et leur propagation. La flexibilité des protéines est analysée à différents niveaux de complexité structurelle, du niveau d'organisation primaire au niveau quaternaire. Chacun des cinq premiers chapitres traite un niveau différent d'organisation structurelle locale avec le premier chapitre traitant des structures secondaires classiques tandis que le second analyse la même chose en utilisant un alphabet structurel - les blocs protéiques. Le troisième chapitre se concentre sur l'impact d'événements physiologiques spéciaux comme les modifications post-traductionnelles et le désordre sur les transitions d'ordre sur la flexibilité des protéines. Ces trois chapitres indiquent une mise en œuvre dépendante du contexte de la flexibilité structurelle dans leur environnement local. Dans les chapitres suivants, des structures plus complexes sont prises en compte. Le chapitre 4 traite de l'intégrine αIIbβ3 impliquée dans des troubles génétiques rares. L'impact des mutations pathologiques sur la flexibilité locale est étudié dans deux domaines rigides de l'intégrine αIIbβ3 ectodomaine. La flexibilité inhérente dans ces domaines est montrée pour moduler l'impact des mutations vers les boucles. Le chapitre 5 traite de la modélisation structurelle et de la dynamique d'une structure protéique plus complexe du récepteur des chimiokines des antigènes du groupe Duffy incorporé dans un système de membrane mimétique érythrocytaire. Le modèle est soutenu par l'analyse phylogénétique la plus complète sur les récepteurs de chimiokines jusqu'à ce jour, comme expliqué dans le dernier chapitre de la thèseProtein structures are highly dynamic in nature contrary to their depiction in crystal structures. A major component of structural dynamics is the inherent protein flexibility. The prime objective of this thesis is to understand the role of the inherent dynamics in protein structures and its propagation. Protein flexibility is analyzed at various levels of structural complexity, from primary to quaternary levels of organization. Each of the first five chapters’ deal with a different level of local structural organization with first chapter dealing with classical secondary structures while the second one analysis the same using a structural alphabet - Protein Blocks. The third chapter focuses on the impact of special physiological events like post-translational modifications and disorder to order transitions on protein flexibility. These three chapters indicate towards a context dependent implementation of structural flexibility in their local environment. In subsequent chapters, more complex structures are taken under investigation. Chapter 4 deals with integrin αIIbβ3 that is involved in rare genetic disorders. Impact of the pathological mutations on the local flexibility is studied in two rigid domains of integrin αIIbβ3 ectodomain. Inherent flexibility in these domains is shown to modulate the impact of mutations towards the loops. Chapter 5 deals with the structural modelling and dynamics of a more complex protein structure of Duffy Antigen Chemokine Receptor embedded in an erythrocyte mimic membrane system. The model is supported by the most comprehensive phylogenetic analysis on chemokine receptors till date as explained in the last chapter of the thesis