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Amyloid fibril structure of peptides and proteins by magic angle spinning NMR spectroscopy and dynamic nuclear polarization

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dc.contributor.advisor Robert G. Griffin. en_US Debelouchina, Galia Tzvetanova en_US
dc.contributor.other Massachusetts Institute of Technology. Dept of Chemistry. en_US 2012-01-12T19:31:22Z 2012-01-12T19:31:22Z 2011 en_US 2011 en_US
dc.description Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2011. en_US
dc.description Vita. Cataloged from student-submitted PDF version of thesis. en_US
dc.description Includes bibliographical references. en_US
dc.description.abstract 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. en_US
dc.description.statementofresponsibility by Galia Tzvetanova Debelouchina. en_US
dc.format.extent 183 p. en_US
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. en_US
dc.rights.uri en_US
dc.subject Dept of Chemistry. en_US
dc.title Amyloid fibril structure of peptides and proteins by magic angle spinning NMR spectroscopy and dynamic nuclear polarization en_US
dc.type Thesis en_US Ph.D. en_US
dc.contributor.department Massachusetts Institute of Technology. Dept of Chemistry. en_US
dc.identifier.oclc 770105742 en_US

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