Rozprawy doktorskie: „Structure and Dynamics of Peptides by NMR Spectroscopy”

1

Tengel, Tobias. "Studies of protein structure, dynamics and protein-ligand interactions using NMR spectroscopy". Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1472.

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Amero, Carlos D. "Protein Function Study by NMR Spectroscopy". The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1205431343.

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3

Debelouchina, Galia Tzvetanova. "Amyloid fibril structure of peptides and proteins by magic angle spinning NMR spectroscopy and dynamic nuclear polarization". Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/68485.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2011.
Vita. Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references.
Amyloid fibrils are insoluble, non-crystalline protein filaments associated with a number of diseases such as Alzheimer's and Type Il diabetes. They can have a functional role in different organisms and many proteins and peptides have been found to form amyloid fibrils in vitro. We have used magic angle spinning (MAS) NMR spectroscopy to investigate the structure of two amyloid fibril systems - an 11- residue segment from the disease-related protein transthyretin (TTR); and P2- microglobulin (32m), a 99-residue protein associated with dialysis-related amyloidosis. The TTR(105-115) case exemplifies our efforts to characterize the hierarchy of structures present in the fibril form, including the organization of the Pstrands into P-sheets (tertiary structure), the P-sheet interface that defines each protofilament (quaternary structure), and the protofilament-to-protofilament contacts that lead to the formation of the complete fibril. Our efforts were guided by information obtained from other methods such as cryo-electron microscopy and atomic force microscopy, and resulted in the very first atomic resolution structure of a complete amyloid fibril. We have extended the methods used in the TTR(105-115) structure determination procedure to the fibrils formed by 2m, a process complicated not only by the much larger size of the protein involved but also by the high degree of dynamics exhibited in these fibrils. Nevertheless, we were able to characterize the secondary structure of the protein in the fibril form, and the tertiary and quaternary interactions within the fibrils. In addition, we have compared at the molecular level @2m fibrils formed under different conditions, in an effort to characterize the origins of fibril polymorphism for this protein sequence. Our work on amyloid fibrils has also benefited extensively from the development of dynamic nuclear polarization, a method used to enhance the sensitivity of MAS NMR experiments, leading to unprecedented gains in signal-to-noise ratios and acquisition times.
by Galia Tzvetanova Debelouchina.
Ph.D.

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4

Unnikrishnan, Aparna. "INVESTIGATION OF PROTEIN STRUCTURE AND DYNAMICS BY NMR SPECTROSCOPY". The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1595418229203869.

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5

Thurgood, Andrew G. P. "NMR studies of the structure and dynamics of proteins and peptides". Thesis, University of East Anglia, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.253623.

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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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7

Conroy, Daniel William. "Structural Studies of Biomolecules by Dynamic Nuclear Polarization Solid-State NMR Spectroscopy". The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555428362333615.

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Nagapudi, Karthik. "Solid-state NMR investigation of structure and dynamics of polyrotaxanes". Thesis, Georgia Institute of Technology, 1997. http://hdl.handle.net/1853/8638.

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Tomaszewski, John William. "Structure and dynamics of small proteins by NMR /". Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/11541.

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Birk, Olsen Helle. "Investigations of structure and dynamics of insulin mutants using NMR spectroscopy /". Roskilde : Department of Life Sciences and Chemistry, Roskilde University, 1996. http://hdl.handle.net/1800/464.

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11

Thirumoorthy, Ramanan. "NMR studies of structure and dynamics of novel peptide-based melanocortin receptor antagonists". [Gainesville, Fla.] : University of Florida, 2002. http://purl.fcla.edu/fcla/etd/UFE1001186.

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12

Drew, Daniel L. Jr. "Investigating the Structure and Dynamic Properties of Bacteriophage S21 Pinholin Using Solid-State Nuclear Magnetic Resonance and Electron Paramagnetic Resonance Spectroscopy". Miami University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=miami1610187893016095.

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13

Dallmann, André. "Structure and dynamics of fluorophore-labelled DNA helices probed by NMR-spectroscopy". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16065.

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Mittels NMR-Spektroskopie werden Störungen in Struktur und Dynamik von DNA untersucht, die durch den Einbau jeweils eines der beiden Fluorophore 2- Aminopurin (2AP) und 2-Hydroxy-7-nitrofluoren (HNF) hervorgerufen werden. Zu diesem Zweck werden die NMR-Strukturen der modifizierten Duplexe mit der Sequenz 5’-GCTGCAXACGTCG-3’ berechnet. Im Fall X=2AP (13mer2AP) ist die Partnerbase im Komplementärstrang ein T, während gegenüber X=HNF (13mer- HNF) eine abasische Stelle eingeführt wird. Durch den Vergleich der Ergebnisse zum 13mer2AP mit denjenigen des entsprechenden unmodifizierten DNA Doppelstranges (13merRef, X=A) konnte jegliche Änderung eindeutig dem Einbau von 2AP zugordnet werden. Für die NMR-Strukturen von 13merRef und 13mer2AP können kleine aber signifikante, über die gesamte Helix verteilte Strukturstörungen nachgewiesen werden. Experimente zum Iminoprotonenaustausch mit Wasser ergeben, daß der Einbau von 2AP die Basenpaarlebensdauern der 7 zentralen Basenpaare erniedrigt. Die kürzere Lebensdauer des 2AP:T Basenpaares kann jedoch nicht den schnellen Wasseraustausch im Sättigungstransfer- Experiment ohne Zugabe von Basenkatalysator erklären. Als Erklärung für diese Diskrepanz wird eine effizientere intrinsische Katalyse vermutet. Als mögliche, katalytisch aktive Stelle wird das T O4 Atom diskutiert, welches über die große Furche leicht zugänglich ist und das keine Wasserstoffbrückenbindung innerhalb des Basenpaares ausbilden kann. Die übergeordnete Struktur des 13merHNF ist eine B-Form DNA Helix. Die NOE Kreuzpeaks zu den Protonen im HNF können jedoch nur durch zwei verschiedene Orientierungen des HNFs in der helikalen Anordnung beschrieben werden. Das Verhältnis der beiden Orientierungen untereinander wird als 1:1 abgeschätzt. Störungen in der Basenpaardynamik werden durch die höhere Linienbreite und die starke Hochfeldverschiebung des T auf der 5’-Seite ausgehend von der abasischen Stelle angedeutet.
Structural and dynamic perturbations in DNA upon incorporation of either fluorophore, 2-Aminopurine (2AP) or 2-Hydroxy-7-nitrofluorene (HNF), are characterized by NMR spectroscopy. For this purpose the NMR solution structures of the modified DNA duplexes with the sequence 5’-GCTGCAXACGTCG-3’ are solved. For X=2AP (13mer2AP) the partner base in the complementary strand is T, while for X=HNF (13merHNF) an abasic site is introduced to avoid steric strain. By comparing results on 13mer2AP with the corresponding unmodified DNA duplex (13merRef, X=A), any perturbation can be unambiguously assigned to 2AP incorporation. For the NMR solution structure of 13merRef and 13mer2AP small but significant changes in helical parameters are found throughout the helix. Imino proton exchange measurements reveal an extended, distributed effect of 2AP incorporation on the lifetimes of the central seven base pair. However, the reduced base pair lifetime of 2AP:T cannot fully account for the rapid water exchange observed with saturation transfer experiments in the absence of base catalyst. This indicates enhanced intrinsic catalysis. As a possible catalytic site the T O4 atom opposite 2AP is discussed, which is easily accessible through the major groove and lacks a hydrogen bonding partner within the base pair. The overall NMR solution structure is found to be B-DNA. However the NOE cross-peaks involving the HNF residue can only be accounted for by two different orientations of the HNF inside the DNA helical stack. Their population ratio is estimated to be 1:1. Dynamical perturbation is indicated by the increased linewidth and strong upfield shift of the T residue to the 5’-side of the abasic site.

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14

Wang, Tuo Ph D. Massachusetts Institute of Technology. "Structure and dynamics of plant cell walls and membrane peptides from solid-state NMR". Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103710.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Solid-state nuclear magnetic resonance (SSNMR) is a powerful technique to study the structure, dynamics and interactions of bio-macromolecules. This thesis mainly focuses on the characterization of the architecture and loosening of primary plant cell walls and the interactions between membrane and peptides. Plant cell wall is a complex system mainly comprising three types of insoluble polysaccharides: cellulose, hemicellulose and pectin. The spatial arrangement of these macromolecules has been largely elusive due to the lack of high-resolution and sitespecific characterization techniques. Here, we introduce SSNMR to investigate the interactions of macromolecules in ¹³C-labeled plant primary cell walls with minimal treatment. Our multidimensional ¹³C spectra show intense cellulose-pectin correlations, suggesting subnanometer contacts between these polymers. The cellulose-pectin interaction is found to be an inherent feature of primary cell walls because it is independent of the hydration history and is caused by site-specific interactions instead of molecular crowding. By measuring water to polysaccharide spin diffusion in intact and sequentially digested walls, we are able to examine the three-dimensional structure of cell walls. Our results suggest a single network model, where cellulose microfibrils make physical contacts with both pectin and hemicellulose. We also investigated how this network was unlocked by expansin, a wall-loosening protein. Using differential isotopic labeling and dynamic nuclear polarization, we determined the binding sites of 0.2 mg expansin in cell walls. Cellulose microfibrils with entrapped hemicellulose were found to be the targets of expansins, thus shedding light on the mechanisms of wall elongation and plant growth. These results have deepened our understanding of plant cell walls, a smart material with both high mechanical strength and extensibility. In addition, we also developed new approaches to investigate the interactions between membranes and peptides. By measuring heteronuclear correlation spectra and proton relaxation times, we determined the localization of the Influenza M2 peptide in distinctly curved membrane domains. Using a rigid-solid heteronuclear correlation experiment, we were able to determine the depth of insertion of dynamically invisible peptides in gel-phase membranes. These studies provide new strategies to study the functionally relevant membrane-curvature induction by proteins and the partitioning and insertion of proteins into lipid membranes.
by Tuo Wang.
Ph. D.

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15

Rapp, Almut. "Structure and dynamics of supramolecular assemblies studied by advanced solid-state NMR spectroscopy". [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969937962.

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Xu, Xiaolin, i Xiaolin Xu. "Theory and Applications of Solid-State NMR Spectroscopy to Biomembrane Structure and Dynamics". Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/626369.

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Solid-state Nuclear Magnetic Resonance (NMR)is one of the premiere biophysical methods that can be applied for addressing the structure and dynamics of biomolecules, including proteins, lipids, and nucleic acids. It illustrates the general problem of determining the average biomolecular structure, including the motional mean-square amplitudes and rates of the fluctuations. Lineshape and relaxtion studies give us a view into the molecular properties under different environments. To help the understanding of NMR theory, both lineshape and relaxation experiments are conducted with hexamethylbezene (HMB). This chemical compound with a simple structure serves as a perfect test molecule. Because of its highly symmetric structure, its motions are not very difficult to understand. The results for HMB set benchmarks for other more complicated systems like membrane proteins. After accumulating a large data set on HMB, we also proceed to develop a completely new method of data analysis, which yields the spectral densities in a body-fixed frame revealing internal motions of the system. Among the possible applications of solid-state NMR spectroscopy, we study the light activation mechanism of visual rhodopsin in lipid membranes. As a prototype of G-protein-coupled receptors, which are a large class of membrane proteins, the cofactor isomerization is triggered by photon absorption, and the local structural change is then propagated to a large-scale conformational change of the protein. Facilitation of the binding of transducin then passes along the visual signal to downstream effector proteins like transducin. To study this process, we introduce 2H labels into the rhodopsin chromophore retinal and the C-terminal peptide of transducin to probe the local structure and dynamics of these two hotspots of the rhodopsin activation process. In addition to the examination of local sites with solid-state 2H NMR spectroscopy, wide angle X-ray scattering (WAXS) provides us the chance of looking at the overall conformational changes through difference scattering profiles. Although the resolution of this method is not as high as NMR spectroscopy, which gives information on atomic scale, the early activation probing is possible because of the short duration of the optical pump and X-ray probe lasers. We can thus visualize the energy dissipation process by observing and comparing the difference scattering profiles at different times after the light activation moments.

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17

Landström, Jens. "Structure, dynamics and interactions of biomolecules : investigations by NMR spectroscopy and computational methods /". Stockholm : Department of Organic Chemistry, Stockholm University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-30120.

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Diss. (sammanfattning) Stockholm : Stockholms universitet, 2009.
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: Submitted. Paper 5: In progress. Paper 6: In progress. Paper 7: Manuscript. Härtill 7 uppsatser.

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Philippopoulos, Marios. "Comparative studies of protein structure and dynamics by molecular dynamics simulation, NMR spectroscopy and x-ray crystallography". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq41038.pdf.

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Flodell, Sara. "Structure and Dynamics of the Hepatitis B Virus Encapsidation Signal Revealed by NMR Spectroscopy". Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-316.

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Brodsky, Alexander S. (Alexander Simon) 1970. "Structure and dynamics of the HIV-2 TAR RNA-argininamide complex by NMR spectroscopy". Thesis, Massachusetts Institute of Technology, 1998. http://hdl.handle.net/1721.1/49982.

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Zhu, Leiming. "A study of spin dynamics and molecular structure of nucleic acids by NMR /". Thesis, Connect to this title online; UW restricted, 1994. http://hdl.handle.net/1773/11543.

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Ying, Jinfa. "Studies of biologically active peptides by NMR and molecular dynamics simulations: From structure and dynamics to design and synthesis". Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280667.

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Nuclear magnetic resonance spectroscopy and molecular dynamics simulation have been used to study the structure and dynamics of biologically active peptide ligands for glucagon and melanocortin receptors, providing valuable insights into the receptor ligand interactions and useful information for the further design of more potent and selective ligands for these receptors. The NMR structure of the potent glucagon antagonist [desHis¹, desPhe⁶, Glu⁹]glucagon amide consists of an unstructured N-terminal segment (2-5), an irregular helix (7-14), a hinge region (15-18), and a well-defined α-helix (19-29). The two helices form an L-shaped structure with an angle of about 90° between the helix axes. There is an extended hydrophobic cluster, which runs along the inner surface of the L-structure and incorporates the side chains of the hydrophobic residues of each of the amphipathic helices. The outer surface contains the hydrophilic side chains. This result is the first clear indication of an overall tertiary fold for a glucagon analogue in the micelle-bound state. In addition to the structural difference, molecular dynamics simulations showed both N- and C-terminal residues in the glucagon antagonist are more highly ordered than those in glucagon. The single helix obtained for glucagon in the crystal state was found to unravel in the simulation around the region approximately corresponding to the hinge region in the antagonist. These results may have important implications for the biological activities of both peptides. The conformational study of cyclic alpha-melanocyte stimulating hormone analogues by NMR showed that their overall backbone structures are similar around the message sequence (His⁶-D-Phe⁷/D-Nal(2')⁷-Arg⁸-Trp⁹). beta-Turns spanning His⁶ and D-Phe⁷/D-Nal(2')⁷ were identified in all analogues. However, a stacking between the aromatic rings of His⁶ and D-Phe⁷/D-Nal⁷ was observed for the melanocortin agonists, but not for the antagonists. Based on the NMR structure of MTII, a library of new alpha-MSH analogues was designed and synthesized with a disulfide or lactam bridge used as a conformational constraint and the pharmacophore group in Arg⁸ mimicked by Nᵅ-alkylation via the Mitsunobu reaction. These new analogues exhibited high binding affinity and selectivity for the human melanocortin-4 receptor, thus suggesting the usefulness of the NMR structural model of α-MSH peptides.

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Guan, Xiao, i 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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Wagstaff, Jane Louise. "Structure, dynamics and interaction studies of integrin avb6 specific peptides using nuclear magnetic resonance spectroscopy". Thesis, University of Kent, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544092.

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Li, Xing. "Structure and dynamics of alamethicin dimers by high-resolution proton and nitrogen-15 NMR spectroscopy". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0026/MQ51741.pdf.

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Li, Xing. "Structure and dynamics of alamethicin dimers by high-resolution proton and nitrogen-15 NMR spectroscopy". Ottawa : National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.nlc-bnc.ca/obj/s4/f2/dsk1/tape2/PQDD%5F0026/MQ51741.pdf.

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Iwakawa, Naoto. "Dynamic Structural Changes of Proteins Revealed by NMR Spectroscopy Under Physicochemical Perturbations". Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263679.

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John, Michael. "Structure and exchange dynamics of the apical domains of the thermosome and human saposins by NMR spectroscopy". [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972320008.

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Abu-Baker, Shadi. "Solid-State NMR Spectroscopic Studies on Phospholamban and Saposin C Proteins in Phospholipid Membranes". Miami University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=miami1185851259.

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Ghimire, Harishchandra. "Structure, Dynamics, and Distance Measurements in Membrane Proteins and Peptides using EPR Spectroscopic Techniques". Miami University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=miami1291739688.

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Hudson, Frederick Michael Lewis. "NMR characterization guides the design of beta hairpins and sheets while providing insights into folding cooperativity and dynamics /". Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8639.

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Gao, Xinfeng. "Studies of the structure and interaction of several neuropeptides in membrane mimics by NMR spectroscopy and molecular dynamics simulation /". free to MU campus, to others for purchase, 2004. http://wwwlib.umi.com/cr/mo/fullcit?p3137700.

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Whittaker, Sara Britt-Marie. "An investigation into the structure and dynamics of the DNase domain of colicin E9 by heteronuclear NMR spectroscopy". Thesis, University of East Anglia, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266728.

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Granata, Daniele. "Characterizing Structure and Free Energy Landscape of Proteins by NMR-guided Metadynamics". Doctoral thesis, SISSA, 2013. http://hdl.handle.net/20.500.11767/4824.

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In the last two decades, a series of experimental and theoretical advances has made it possible to obtain a detailed understanding of the molecular mechanisms underlying the folding process of proteins. With the increasing power of computer technology, as well as with the improvements in force fields, atomistic simulations are also becoming increasingly important because they can generate highly detailed descriptions of the motions of proteins. A supercomputer specifically designed to integrate the Newton's equations of motion of proteins, Anton, has been recently able to break the millisecond time barrier. This achievement has allowed the direct calculation of repeated folding events for several fast-folding proteins and to characterize the molecular mechanisms underlying protein dynamics and function. However these exceptional resources are available only to few research groups in the world and moreover the observation of few event of a specific process is usually not enough to provide a statistically significant picture of the phenomenon. In parallel, it has also been realized that by bringing together experimental measurements and computational methods it is possible to expand the range of problems that can be addressed. For example, by incorporating structural informations as structural restraints in molecular dynamics simulations it is possible to obtain structural models of these transiently populated states, as well as of native and non-native intermediates explored during the folding process. By applying this strategy to structural parameters measured by nuclear magnetic resonance (NMR) spectroscopy, one can determine the atomic-level structures and characterize the dynamics of proteins. In these approaches the experimental information is exploited to create an additional term in the force field that penalizes the deviations from the measured values, thus restraining the sampling of the conformational space to regions close to those observed experimentally. In this thesis we propose an alternative strategy to exploit experimental information in molecular dynamics simulations. In this approach the measured parameters are not used as structural restraints in the simulations, but rather to build collective variables within metadynamics calculations. In metadynamics , the conformational sampling is enhanced by constructing a time-dependent potential that discourages the explorations of regions already visited in terms of specific functions of the atomic coordinates called collective variables. In this work we show that NMR chemical shifts can be used as collective variables to guide the sampling of conformational space in molecular dynamics simulations. Since the method that we discuss here enables the conformational sampling to be enhanced without modifying the force field through the introduction of structural restraints, it allows estimating reliably the statistical weights corresponding to the force field used in the molecular dynamics simulations. In the present implementation we used the bias exchange metadynamics method, an enhanced sampling technique that allows reconstructing the free energy as a simultaneous function of several variables. By using this approach, we have been able to compute the free energy landscape of two different proteins by explicit solvent molecular dynamics simulations. In the application to a well-structured globular protein, the third immunoglobulin-binding domain of streptococcal protein G (GB3), our calculation predicts the native fold as the lowest free energy minimum, identifying also the presence of an on-pathway compact intermediate with non-native topological elements. In addition, we provide a detailed atomistic picture of the structure at the folding barrier, which shares with the native state only a fraction of the secondary structure elements. The further application to the case of the 40-residue form of Amyloid beta, allows us another remarkable achievement: the quantitative description of the free energy landscape for an intrinsically disordered protein. This kind of proteins are indeed characterized by the absence of a well-defined three-dimensional structure under native conditions and are therefore hard to investigate experimentally. We found that the free energy landscape of this peptide has approximately inverted features with respect to normal globular proteins. Indeed, the global minimum consists of highly disordered structures while higher free energy regions correspond to partially folded conformations. These structures are kinetically committed to the disordered state, but they are transiently explored even at room temperature. This makes our findings particularly relevant since this protein is involved in the Alzheimer's disease because it is prone to aggregate in oligomers determined by the interaction of the monomer in extended beta-strand organization, toxic for the cells. Our structural and energetic characterization allows defining a library of possible metastable states which are involved in the aggregation process. These results have been obtained using relatively limited computational resources. The total simulation time required to reconstruct the thermodynamics of GB3 for example is about three orders of magnitude less than the typical timescale of folding of similar proteins, simulated also by Anton. We thus anticipate that the technique introduced in this thesis will allow the determination of the free energy landscapes of wide range of proteins for which NMR chemical shifts are available. Finally, since chemical shifts are the only external information used to guide the folding of the proteins, our methods can be also successfully applied to the challenging purpose of NMR structure determination, as we have demonstrated in a blind prediction test on the last CASD-NMR target.

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Sahakyan, Aleksandr B. "Extending the boundaries of the usage of NMR chemical shifts in deciphering biomolecular structure and dynamics". Thesis, University of Cambridge, 2012. https://www.repository.cam.ac.uk/handle/1810/243642.

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NMR chemical shifts have an extremely high information content on the behaviour of macromolecules, owing to their non-trivial dependence on myriads of structural and environmental factors. Although such complex dependence creates an initial barrier for their use for the characterisation of the structures of protein and nucleic acids, recent developments in prediction methodologies and their successful implementation in resolving the structures of these molecules have clearly demonstrated that such barrier can be crossed. Furthermore, the significance of chemical shifts as useful observables in their own right has been substantially increased since the development of the NMR techniques to study low populated 'excited' states of biomolecules. This work is aimed at increasing our understanding of the multiple factors that affect chemical shifts in proteins and nucleic acids, and at developing high-quality chemical shift predictors for atom types that so far have largely escaped the attention in chemical shift restrained molecular dynamics simulations. A general approach is developed to optimise the models for structure-based chemical shift prediction, which is then used to construct CH3Shift and ArShift chemical shift predictors for the nuclei of protein side-chain methyl and aromatic moieties. These results have the potential of making a significant impact in structural biology, in particular when taking into account the advent of recent techniques for specific isotope labelling of protein side-chain atoms, which make large biomolecules accessible to NMR techniques. Through their incorporation as restraints in molecular dynamics simulations, the chemical shifts predicted by the approach described in this work create the opportunity of studying the structure and dynamics of proteins in a wide range of native and non-native states in order to characterise the mechanisms underlying the function and dysfunction of these molecules.

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Shannon, Matthew D. "High Resolution Structural and Dynamic Studies of Biomacromolecular Assemblies using Solid-State NMR Spectroscopy". The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1534321838601796.

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Kim, Gunwoo. "Understanding local structure and dynamics of the proton-conducting solid electrolytes CsH₂PO₄ and CsH(PO₃H) by solid-state NMR spectroscopy". Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708211.

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Iordanov, Iordan. "Structure and dynamics of the outer membrane protein A from Klebsiella pneumoniae : a joint NMR–SMFS–proteolysis and MS approach". Toulouse 3, 2012. http://thesesups.ups-tlse.fr/1602/.

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"KpOmpA est une protéine de la membrane externe de K. Pneumoniae. Elle fait partie de la famille des "outer membrane protein A", OmpA. KpOmpA est une protéine constituée de deux domaines: un domaine transmembranaire structuré en tonneau ß et une partie soluble, périplasmique. Le domaine transmembranaire de KpOmpA présente une homologie importante avec celle d'OmpA d'E. Coli dont la structure a été déterminée par cristallographie aux rayons X et spectroscopie RMN. OmpA d'E. Coli est responsable lors de la formation de biofilm. Elle a un rôle d'adhésine et d'invasine. Elle est la cible préférentielle du système immunitaire et est le récepteur de bactériophages. Il est admis que la plupart de ces fonctions sont dues aux boucles extracellulaires de ces protéines. Les différences majeures entre les protéines KpOmpA et OmpA d'E. Coli concernent les boucles extracellulaires de longueur plus importante dans le cas de KpOmpA. Elles jouent un rôle important au cours de l'activation des macrophages et des cellules dendritiques par la voie des récepteurs TLR2. Les boucles extracellulaires jouent un rôle essentiel au cours de l'activation du système immunitaire. Mieux définir la structure et la dynamique de ces boucles est d'une importance essentielle afin de mieux appréhender la fonctionnalité des boucles extracellulaires de KpOmpA. Les informations structurales connues actuellement (structure RMN déterminée dans le groupe IPBS RMN en 2009) ont été obtenus jusqu'à présent avec des échantillons de protéines recombinantes purifiées et repliées dans des micelles de détergent. Dans le présent travail, nous avons d'abord établi un protocole de reconstitution de la protéine dans une membrane phospholipidique et caractérisé nos échantillons par microscopie électronique. Des expériences de spectroscopie de force atomique sur molécule unique ont été réalisées pour caractériser le repliement de la protéine dans son environnement membranaire. Ces expériences suggèrent un nouveau rôle de KpOmpA au sein même de la membrane (collaboration D. Müller, ETH Zürich). Le domaine soluble périplasmique de la protéine a été exprimé indépendamment du domaine membranaire. Les premières expériences HSQC réalisées montrent une structuration de ce domaine. La structure de ce domaine par spectroscopie RMN est en cours de réalisation. Le comportement dynamique des boucles extracellulaires du domaine membranaire KpOmpA reconstitué dans des liposomes a été étudié par spectroscopie RMN à l'angle magique (MAS) et notamment par mesure des temps de relaxation. Nous avons montré que la dynamique intrinsèque de la protéine est indépendante de l'environnement (membrane vs micelle). Des expériences de protéolyse ménagée suivie par spectrométrie de masse (MALDI-TOF) ont été comparées avec les informations RMN afin d'évaluer plus précisément les niveaux de mobilité des différentes boucles extracellulaires. La préservation au cours de l'évolution des boucles extracellulaires semble lier à leur dynamique, ce qui suggère l'importance de ces boucles extracellulaires, en termes de séquence, longueur mais aussi de dynamique lors de la réponse immunitaire. "
KpOmpA is a two-domain membrane protein from Klebsiella pneumoniae belonging to the outer membrane protein A (OmpA) family. It is composed of a transmembrane ß-barrel with 8 ß-strands and a C-terminal, soluble periplasmic domain. The transmembrane domain presents a significant homology with E. Coli OmpA whose three dimensional structure has been determined by X-ray crystallography and by NMR. The E. Coli homologue can function as an adhesin and invasin, participate in biofilm formation, act as both an immune target and evasin, and serves as a receptor for several bacteriophages. It is assumed that most of these functions involve the four protein loops that emanate from the protein to the exterior of the cell. The difference between KpOmpA and E. Coli OmpA is mostly concentrated in these extracellular loops which are larger in the case of KpOmpA. KpOmpA was shown to activate macrophages and dendritic cells through the TLR2 dependent pathway, and these larger loops are supposed to play a specific role in the interactions with the immune system. Thus the structure and dynamics of these loops is of prime functional significance. The currently available information in this regard, including the NMR structure determined in the IPBS NMR group in 2009, have been obtained so far with recombinant protein samples purified and refolded in detergent micelles. In the present work we first established a reconstitution protocol that allowed the incorporation of the membrane protein in the more native environment of the lipid bilayer and characterised our samples by electron microscopy. SMFS experiments were used to probe the reconstituted KpOmpA unfolding-refolding pathways, exploring the folding mechanisms for ß-barrel proteins and suggesting a novel role for OmpA in the bacterial membrane (in collaboration with the group of D. Müller, ETH Zürich). The C-terminal periplasmic domain of KpOmpA was expressed and purified as a separate product and the feasibility of its structure elucidation by NMR was demonstrated by obtaining a high quality HSQC spectrum. The dynamic behaviour of the extracellular portion of the KpOmpA membrane domain reconstituted in liposomes has been investigated by solid state MAS NMR relaxation experiments. We confirmed that the previously observed gradient of dynamic along the molecule axis is an intrinsic property of the protein. Limited proteolysis and MALDI-TOF experiments were coupled with the NMR information in order to assess more precisely the different mobility levels in the loops. Evolutional preservation of the different loops regions is related to their observed flexibility, pointing towards immunologically important, variable, dynamic and accessible loops sections

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Lignell, Martin. "Structural Transitions in Helical Peptides : The Influence of Water – Implications for Molecular Recognition and Protein Folding". Doctoral thesis, Uppsala universitet, Kemisk fysik, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-109396.

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Fluctuations in protein structure are vital to function. This contrasts the dominating structure-function paradigm, which connects the well-defined three-dimensional protein structure to its function. However, catalysis is observed in disordered enzymes, which lack a defined structure. Disordered proteins are involved in molecular recognition events as well. The aim of this Thesis is to describe the structural changes occuring in protein structure and to investigate the mechanism of molecular recognition. Protein architecture is classified in a hierarchical manner, that is, it is categorized into primary, secondary, and tertiary levels. One of the major questions in biology today is how proteins fold into a defined three-dimensional structure. Some protein folding models, like the framework model, suggest that the secondary structure, like α-helices, is formed before the tertiary structure. This Thesis raises two questions: First, are structural fluctuations that occur in the protein related to the folding of the protein structure? Second, is the hierarchic classification of the protein architecture useful to describe said structural fluctuations? Kinetic studies of protein folding show that important dynamical processes of the folding occur on the microsecond timescale, which is why time-resolved fluorescence spectroscopy was chosen as the principal method for studying structural fluctuations in the peptides. Time-resolved fluorescence spectroscopy offers a number of experimental advantages and is useful for characterizing typical structural elements of the peptides on the sub-microsecond timescale. By observing the fluorescence lifetime distribution of the fluorescent probe, which is a part of the hydrophobic core of a four-helix bundle, it is shown that the hydrophobic core changes hydration state, from a completely dehydrated to a partly hydrated hydrophobic core. These fluctuations are related to the tertiary structure of the four-helix bundle and constitute structural transitions between the completely folded four-helix bundle and the molten globule version. Equilibrium unfolding of the four-helix bundle, using chemical denaturants or increased temperature, shows that the tertiary structure unfolds before the secondary structure, via the molten globule state, which suggests a hierarchic folding mechanism of the four-helix bundle. Fluctuations of a 12 amino acid long helical segment, without tertiary structure, involve a conformational search of different helical organizations of the backbone. Binding and recognition of a helix-loop-helix to carbonic anhydrase occurs through a partly folded intermediate before the final tertiary and bimolecular structure is formed between the two biomolecules. This confirms the latest established theory of recognition that the binding and the folding processes are coupled for the binding molecules.

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Hanni, M. (Matti). "Static and dynamic NMR properties of gas-phase xenon". Doctoral thesis, University of Oulu, 2011. http://urn.fi/urn:isbn:9789514294570.

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Abstract This thesis presents computational studies of both the static and dynamic parameters of the nuclear magnetic resonance (NMR) spectroscopy of gaseous xenon. First, state-of-the-art static magnetic resonance parameters are computed in small xenon clusters by using methods of quantum chemistry, and second, time-dependent relaxation phenomena are investigated via molecular dynamics simulations at different experimental conditions. Based on the underlying quantum and classical mechanics concepts, computational methods represent a procedure complementary to experiments for investigating the properties of atoms, molecules, clusters and solids. Static NMR spectral parameters, chemical shift, shielding anisotropy and asymmetry parameter, nuclear quadrupole coupling, and spin-rotation coupling, are calculated using different electronic structure methods ranging from the uncorrelated Hartree-Fock method to correlated second-order Møller-Plesset many-body perturbation, complete/restricted active space multiconfiguration self-consistent field, and to coupled-cluster approaches. The bond length dependence of these properties is investigated in the xenon dimer (Xe2). A well-characterized property in experimental NMR, the second virial coefficient of nuclear shielding, is theoretically calculated by a variety of methods and convincingly verified against experimental findings. Here, it is mandatory to include effects from special relativity as well as electron correlation. As a side result, a purely theoretical potential energy curve for Xe2, comparable to best experimental ones, is calculated. A pairwise additive scheme is established to approximate the NMR properties in differently coordinated sites of xenon clusters Xen (n = 2 - 12). Especially the pairwise additive chemical shift values are found to be in close agreement with quantum-chemical results and only a small scaling factor close to unity is needed for the correct behavior. Finally, a dynamical magnetic resonance property, the experimental nuclear spin-lattice relaxation rate R1 of monoatomic Xe gas due to the chemical shift anisotropy (CSA) mechanism is validated from first principles. This approach is based on molecular dynamics simulations over a large range of temperatures and densities, combined with the pairwise additive approximation for the shielding tensor. Therein, the shielding time correlation function is seen to reflect the characteristic time scales related to both interatomic collisions and cluster formation. For the first time, the physics of gaseous xenon is detailed in full in the context of CSA relaxation.

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Jean-François, Frantz. "Vers un nouveau mode d’action de peptides antimicrobiens structurés en feuillets ß : formation de domaines membranaires par la cateslytine". Thesis, Bordeaux 1, 2008. http://www.theses.fr/2008BOR13638/document.

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Le peptide antimicrobien Cateslytine (bCGA RSMRLSFRARGYGFR ) inhibe la libération des catécholamines des cellules chromaffines. Des études biologiques ont montré que ce peptide est capable d’inhiber aussi la croissance de nombreux microorganismes notamment des bactéries, des levures ainsi que le parasite Plasmodium falciparum responsable de la malaria. Cependant, le mode d’action moléculaire demeurait inconnu. Afin de mieux comprendre le ciblage et la sélectivité de ce peptide sur les membranes de mammifères ou de microorganismes, nous avons donc envisagé la reconstitution du système biologique composé initialement de peptides en contact avec des cellules, en le substituant par des modèles de membrane, de composition mimant celle des différents microorganismes. Des études structurales ont été menées en utilisant la technique d’ATR-FTIR polarisé, le dichroïsme circulaire et la RMN à haute résolution. La dynamique membranaire a été étudiée en utilisant la RMN des solides du phosphore et du deutérium. Des expériences de patch-clamp ont été effectuées afin de mesurer des flux d’ions au travers de la membrane. Enfin, de la simulation par ordinateur a permis de comprendre cette interaction au niveau moléculaire. Trois résultats principaux sont ressortis de cette approche pluridisciplinaire : i) Des flux ioniques au travers de la membrane attestent de la présence de cannaux. ii) La formation de domaines membranaires rigides constitués de lipides chargés négativement est démontrée. iii) Une structuration des peptides en feuillets ß antiparallèles est observée sur des membranes chargées négativement mimant les microorganismes. L’ensemble de ces résultats conduit à la proposition d’un mode d’action dans lequel la déstabilisation membranaire est induite par les domaines rigides stabilisés par les agrégats de peptides structurés en feuillets ß
The antimicrobial peptide Cateslytin (bCGA RSMRLSFRARGYGFR ) is a five positively charged arginin rich peptide known to inhibit the release of catecholamine in chromaffin granules. Although biological data showed that it is able to inhibit the growth of several microorganisms such as bacteria, yeast and Plasmodium falciparum parasite involved in malaria, the mechanism of action has not been yet studied. In order to better understand both targeting and selectivity of this peptide towards microorganisms, model membranes of variable compositions have been chosen to respectively mimic microorganisms or mammalian membranes. Structural studies have been performed using polarised ATR-FTIR, circular dichroïsm and high resolution NMR Membrane dynamics has been followed using deuterium labelled lipids and solid state NMR Patch clamp experiments were also performed on lipid vesicles to measure channe conductivity. All-atom molecular dynamics on hydrated peptide-lipid membrane systems was also used to assess the interaction from the atomic level. Main results from this interdisciplinary approach are three-fold. i) Electric current passages through membranes demonstrate permeation akin to pore formation. ii) Peptide-induced formation of rigid domains mainly made of negatively charged lipids is found. iii) Peptide antiparallel ß-sheets are observed preferentially with negatively charged lipids mimicking microorganism membranes. The general picture leads to the proposal that membrane destabilization/permeation is promoted by rigid domains stabilised by peptide ß-sheets

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Asami, Sam [Verfasser], Bernd [Akademischer Betreuer] Reif, Andreas [Akademischer Betreuer] Möglich i Hartmut [Akademischer Betreuer] Oschkinat. "Method development for biomolecular solid-state NMR spectroscopy : accessing structure and dynamics of biomolecules in the solid-state / Sam Asami. Gutachter: Bernd Reif ; Andreas Möglich ; Hartmut Oschkinat". Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://d-nb.info/1060425262/34.

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Asami, Sam [Verfasser], Bernd Akademischer Betreuer] Reif, Andreas [Akademischer Betreuer] Möglich i Hartmut [Akademischer Betreuer] [Oschkinat. "Method development for biomolecular solid-state NMR spectroscopy : accessing structure and dynamics of biomolecules in the solid-state / Sam Asami. Gutachter: Bernd Reif ; Andreas Möglich ; Hartmut Oschkinat". Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://nbn-resolving.de/urn:nbn:de:kobv:11-100220957.

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Migliore, Mattia. "Recherche par modélisaion moléculaire de signatures RMN et DC caractéristiques pour les coudes β et y dans les peptides bioactifs. Characterization of β-turns by electronic circular dichroism spectroscopy : a coupled molecular dynamics and time-dependent density functional theory computational study". Thesis, Normandie, 2020. http://www.theses.fr/2020NORMR001.

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Ce travail de thèse a porté sur la recherche, par modélisation moléculaire, de signatures RMN et DC caractéristiques pour les coudes γ et β dans les peptides bioactifs. Les coudes γ et β, avec les hélices, constituent des motifs privilégiés de reconnaissance des peptides bioactifs par leurs cibles. Or, bien qu’il existe, au sein des structures de polypeptides, plusieurs catégories de coudes possédant des géométries différentes (2 types de coudes γ et 12 types de coudes β), peu d’outils expérimentaux sont disponibles pour aider à leur distinction. Ainsi, seuls 4 types de coudes β (I, I’, II et II’) ont, pour l’instant été caractérisés par RMN et il n’existe pas de spectre DC de référence fiable pour aucun motif de type coude. Dans un premier temps, afin d’élargir la base de données de RMN pour tous les types de coudes β (I, I’, II, II’, IV₁, IV₂, IV₃, IV₄, Via1, Via2, VIb et VIII) et γ (classique et inverse), nous avons analysé les paramètres structuraux caractéristiques de RMN (distances inter-hydrogènes et constantes de couplages ᶾJʜɴ-ʜꭤ) sur un ensemble de peptides modèles, extraits de la banque de protéines PDB et représentatifs de ces coudes. Les analyses des distances inter-hydrogènes ont permis d’identifier des signatures RMN caractéristiques pour différencier les deux types de coudes γ et certains types de coudes β (IV₁, IV₂,, VIb et VIII). La constante de couplage ᶾJʜɴ-ʜꭤ pourra servir à confirmer l’identification et à lever des ambiguïtés. Dans un second temps, en couplant dynamique moléculaire et TDDFT, nous avons simulé les spectres de DC de référence de peptides modèles adoptant des conformations de coudes β de type I, I’, II et II’. Les simulations ont permis de discerner deux familles de spectres DC caractéristiques : les types I/II’ d’un côté et les types I’/II de l’autre. L’ensemble de ces résultats indique que les coudes ne présentent pas nécessairement les mêmes signatures pour les deux techniques. La combinaison des signatures discriminantes de RMN et de DC pourrait donc permettre une meilleure identification des natures et des différents types de coudes
The aim of this work is to identify NMR and CD characteristic patterns for β- and γ-turns in bioactive peptides by molecular modelling. With helices, β- and γ-turns constitute favoured recognition motifs in bioactive peptides by their targets. Even though several classes of turns with different geometries exist in polypeptide structures (2 γ-turn types and 12 β-turn types), few experimental tools are available for their characterization. Thus, only 4 types of β-turns (I, I’, II et II’) have been, at present, described by NMR and there are no reliable reference CD spectra for turns. In order to extend the NMR data for all β- and γ-turn types, we analyzed NMR structural parameters (inter-hydrogen distances and ᶾJʜɴ-ʜꭤ coupling constants) in a representative peptide model dataset extracted from the PDB. The inter-hydrogen distance analysis allowed to identify specific NMR patterns for the two γ-turn types and for four β-turn types (IV₁, IV₂,, VIb and VIII). ᶾJʜɴ-ʜꭤ coupling constant may be used to confirm the identification and to remove ambiguities. Then, we simulated the reference CD spectra of model peptides adopting type I, I’, II and II’ β-turn conformations by combining molecular dynamic simulations and TDDFT computations. These computations allowed to determine two families of specific CD spectra : types I/II’, on one side and types I’/II, on the other. All these results indicate that the turns do not present the same patterns in both techniques. The combination of NMR and CD could therefore allow a better identification of the nature and the different types of turns

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Weinhaeupl, Katharina. "Etudes de structure, interactions et dynamique dans des complexes de protéines "chaperone" à l'échelle atomique par spectroscopie RMN". Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAV002.

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Les chaperons moléculaires, une famille de protéines diverses en structure et taille, sont dédiés à accompagner, replier et protéger d’autres protéines afin qu’elles atteignent leur conformation finale et leur emplacement dans la cellule. Dans ce but, les chaperons moléculaires doivent être hautement spécialisés dans l’exécution de tâches spécifiques, telles que le repliement, le transport ou la désagrégation, et polyvalents dans leur motifs de reconnais- sance, afin de pouvoir interagir avec un grand nombre de protéines di érentes. Di érents chaperons moléculaires collaborent au sein de la cellule, formant ainsi un réseau complexe qui assure le contrôle de la qualité du protéome. Les interactions entre les di érents partenaires de ce réseau et entre les chap- erones et leurs substrats sont souvent dynamiques, ce qui rend leur obser- vation structurale particulièrement di cile pour les techniques de biologie structurale. Par conséquent, il y a à ce jour peu d’information sur les struc- tures et mécanismes d’interaction au sein des complexes chaperon-substrate. Dans cette thèse, je présente des études sur la structure, la dynamique et les interactions entre les substrats de deux chaperons moléculaires, en utilisant diverses méthodes biophysiques et in vivo.Dans la première partie, je montre que la chaperone TIM910, située dans l’espace inter-membranaire des mitochondries, lie ses substrats, des protéines membranaires destinées aux deux membranes mitochondriales, d’une manière très dynamique. Non seulement le complexe TIM910 est en échange constant entre les espèces monomèriques et hexameriques, mais aussi le substrat lié échange entre mulitples conformations à une échelle de millisecondes. Sur la base de la résonance magnétique nucléaire (RMN), de small-angle X-ray scat- tering (SAXS), de l’ultracentrifugation analytique (AUC) et des expériences mutationnelles in vivo et des tests fonctionnels d’import dans les mitochon- dries, je propose un modèle structurale de l’interaction entre le chaperon et la protéine membranaire. TIM910 lie ses substrats dans une poche hydrophobe à l’extérieur du chaperon. Cette interaction est modulaire et se fait avec un ou deux hexamères de TIM910, en fonction de la longueur du substrat.Dans la deuxième partie, nous avons étudié le comportement du récepteur N-terminal du unfoldase ClpC1 de M. tuberculosis en présence d’antibiotiques et de ligands di érents. Le domaine N-terminal de ClpC1 est le site de liai- son de divers antibiotiques nouveaux contre M. tuberculosis. L’antibiotique Cyclomarin A supprime complètement la dynamique induite par le ligand arginine-phosphate. Nous proposons que cette suppression de la dynamique soit le principe fondamental du mécanisme d’action de cet antibiotique.Dans les deux cas, les structures X-ray des chaperons dans leur état apo et la structure de ClpC-NTD liée à des antibiotiques étaient disponibles, mais ces structures statiques ne su sent pas pour expliquer le mécanisme d’action. La structure X-ray de TIM910 n’a pas fourni d’ indication sur l’endroit ou la façon dont les substrats sont liés. De même, les structures X-ray du domaine N-terminal de apo et de Cyclomarine A de ClpC1 ne présentent que des di érences de structure mineures. Les deux exemples montrent que les données structurelles statiques souvent ne permettent pas d’expliquer le fonctionnement d’un système moléculaire, donc la combinaison de di érentes techniques et le développement de nouvelles méthodes pour étudier les complexes chaperon-substrat sont primordiaux pour comprendre leur fonction
The diverse group of molecular chaperones is dedicated to accompany, fold and protect other proteins until they reach their final conformation and loca- tion inside the cell. To this end, molecular chaperones need to be specialized in performing specific tasks, like folding, transport or disaggregation, and versatile in their recognition pattern to engage many di erent client pro- teins. Moreover, molecular chaperones need to be able to interact with each other and with other components of the protein quality control system in a complex network. Interactions between the di erent partners in this network and between the substrate and the chaperone are often dynamic processes, which are especially di cult to study using standard structural biology tech- niques. Consequently, structural data on chaperone/substrate complexes are sparse, and the mechanisms of chaperone action are poorly understood. In this thesis I present investigations of the structure, dynamics and substrate- interactions of two molecular chaperones, using various biophysical and in vivo methods.In the first part I show that the mitochondrial membrane protein chap- erone TIM910 binds its substrates in a highly dynamic manner. Not only is the TIM910 complex in constant exchange between monomeric and hex- americ species, but also the bound substrate samples multiple conformations on a millisecond timescale. Based on nuclear magnetic resonance (NMR), small-angle X-ray scattering (SAXS), analytical ultracentrifugation (AUC) and in vivo mutational experiments I propose a structural model of the chap- erone/membrane protein interaction. TIM910 binds its substrates in a hy- drophobic pocket on the exterior of the chaperone in a modular fashion, where the number of TIM910 complexes bound depends on the length of the substrate.In the second part I studied the behavior of the N-terminal receptor do- main of the ClpC1 unfoldase from M.tuberculosis in the presence of di erent antibiotics and ligands. The N-terminal domain of ClpC1 is the binding site for various new antibiotics against M.tuberculosis. The antibiotic cyclomarin completely abolishes dynamics induced by the ligand arginine-phosphate. We propose that this suppression of dynamics is the underlying principle for the mechanism of action of this antibiotic.In both cases X-ray structures of the apo or antibiotic bound form were available, but not su cient to explain the mechanism of action. The X- ray structure of TIM910 provided no evidence on where or how substrates are bound. Likewise, X-ray structures of the apo and cyclomarin-bound N-terminal domain of ClpC1 show only minor di erences in structure.Both examples show that static structural data is often not enough to explain how a molecular system works, and only the combination of di er- ent techniques, including newly developed methods enable the atomic-level understanding of chaperone/substrate complexes

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Li, Xuesong. "Synthesis and physical properties of helical nanosized quinoline-based foldamers : structure, dynamics and photoinduced electron transport". Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0013/document.

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Ce travail présente la synthèse, la caractérisation et l’utilisation (transfert électronique photo-induit) de foldamères de taille nanométriques constitués d’unité quinolines. Grâce a une stratégie de synthèse de doublement de segment une grande variété d’oligomères (jusqu’à 96 unités) ont pu être préparé à partir du synthon 8 aminoquinoline-2-carboxylate.Leurs propriétés dynamiques de ces objets ont été étudiées en solution et en phase gazeuse. La spectrométrie de masse de mobilité ionique a permis de déterminer leur conformation en phase gazeuse. Les expériences de RMN DOSY et d’anisotropie de Fluorescence ont permis de déterminer leurs propriétés de diffusion (transrationnelle et rotationnelle). Ces résultats ont révélés qui ces foldamères sont rigides et que leur architecture hélicoïdale est conservée.Le transport électronique photo-induit à travers ces foldamères de taille nanométrique ont été étudié et le mécanisme de transfert ainsi que son efficacité ont été déterminé pour une série de composés de tailles variables
Herein, synthesis, characterization and application (photoinduced electron transport) of nanosized quinoline-based foldamers have been explored. With double segment strategy, a variety of helical nanosized foldamers (up to 96 quinoline units) were successfully prepared based on 8-aminoquinoline-2-carboxylic acid monomer.The dynamic properties in gas phase and solution were investigated. Ion mobility mass spectrometry afforded access to the conformation state of foldamers ingas phase; DOSY and fluorescence anisotropy assessed the diffusion (translational and rotational, respectively) of foldamers in solution. All of these techniques revealed that quinoline-based foldamers are rigid and that helical conformation is conserved. Photoinduced electron transport through nanosized foldamer was also studied and the mechanism and the transport ratios were revealed

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Andronesi, Ovidiu-Cristian. "Solid-state NMR of (membrane) protein complexes novel methods and applications /". Doctoral thesis, [S.l.] : [s.n.], 2006. http://webdoc.sub.gwdg.de/diss/2006/andronesi.

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Abd, Rahim Munirah Sufiyah [Verfasser], Sonja A. [Akademischer Betreuer] Dames, Bernd [Gutachter] Reif i Sonja A. [Gutachter] Dames. "Characterization of the structure, dynamics and immersion properties of the membrane-associating FATC domain of ataxia telangiectasia mutated by solution NMR spectroscopy and complementary methods / Munirah Sufiyah Abd Rahim ; Gutachter: Bernd Reif, Sonja A. Dames ; Betreuer: Sonja A. Dames". München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1182536360/34.

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Lundborg, Magnus. "Computer-Assisted Carbohydrate Structural Studies and Drug Discovery". Doctoral thesis, Stockholms universitet, Institutionen för organisk kemi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-56411.

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Carbohydrates are abundant in nature and have functions ranging from energy storage to acting as structural components. Analysis of carbohydrate structures is important and can be used for, for instance, clinical diagnosis of diseases as well as in bacterial studies. The complexity of glycans makes it difficult to determine their structures. NMR spectroscopy is an advanced method that can be used to examine carbohydrates at the atomic level, but full assignments of the signals require much work. Reliable automation of this process would be of great help. Herein studies of Escherichia coli O-antigen polysaccharides are presented, both a structure determination by NMR and also research on glycosyltransferases which assemble the polysaccharides. The computer program CASPER has been improved to assist in carbohydrate studies and in the long run make it possible to automatically determine structures based only on NMR data. Detailed computer studies of glycans can shed light on their interactions with proteins and help find inhibitors to prevent unwanted binding. The WaaG glycosyltransferase is important for the formation of E. coli lipopolysaccharides. Molecular docking analyses of structures confirmed to bind this enzyme have provided information on how inhibitors could be composed. Noroviruses cause gastroenteritis, such as the winter vomiting disease, after binding human histo-blood group antigens. In one of the projects, fragment-based docking, followed by molecular dynamics simulations and binding free energy calculations, was used to find competitive binders to the P domain of the capsid of the norovirus VA387. These novel structures have high affinity and are a very good starting point for developing drugs against noroviruses. The protein targets in these two projects are carbohydrate binding, but the techniques are general and can be applied to other research projects.
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Submitted. Paper 5: Manuscript. Paper 6. Manuscript.

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Rodgers, Christopher T. "Magnetic field effects in chemical systems". Thesis, University of Oxford, 2007. http://ora.ox.ac.uk/objects/uuid:f5878b88-c5ba-4cbd-83af-857431aef66e.

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Magnetic fields influence the rate and/or yield of chemical reactions that proceed via spin correlated radical pair intermediates. The field of spin chemistry centres around the study of such magnetic field effects (MFEs). This thesis is particularly concerned with the effects of the weak magnetic fields B₀ ~ 1mT relevant in the ongoing debates on the mechanism by which animals sense the geomagnetic field and on the putative health effects of environmental electromagnetic fields. Relatively few previous studies have dealt with such weak magnetic fields. This thesis presents several new theoretical tools and applies them to interpret experimental measurements. Chapter 1 surveys the development and theory of spin chemistry. Chapter 2 introduces the use of Tikhonov and Maximum Entropy Regularisation methods as a new means of analysing MARY field effect data. These are applied to recover details of the diffusive motion of reacting pyrene and N,N-dimethylaniline radicals. Chapter 3 gives a fresh derivation and appraisal of an approximate, semiclassical approach to MFEs. Monte Carlo calculations allow the elucidation of several "rules of thumb" for interpreting MFE data. Chapter 4 discusses recent optically-detected zero-field EPR measurements, adapting the gamma-COMPUTE algorithm from solid state NMR for their interpretation. Chapter 5 explores the role of RF polarisation in producing MFEs. The breakdown in weak fields of the familiar rotating frame approximation is analysed. Chapter 6 reviews current knowledge and landmark experiments in the area of animal magnetoreception. The origins of the sensitivity of European robins Erithacus rubecula to the Earth’s magnetic field are given particular attention. In Chapter 7, Schulten and Ritz’s hypothesis that avian magnetoreception is founded on a radical pair mechanism (RPM) reaction is appraised through calculations in model systems. Chapter 8 introduces quantitative methods of analysing anisotropic magnetic field effects using spherical harmonics. Chapter 9 considers recent observations that European robins may sometimes be disoriented by minuscule RF fields. These are shown to be consistent with magnetoreception via a radical pair with no (effective) magnetic nuclei in one of the radicals.

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