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Prediction of parallel in-register amyloidogenic beta-structures In highly beta-rich protein sequences by pairwise propensity analysis

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dc.contributor.advisor Bonnie Berger and Susan L. Lindquist. en_US
dc.contributor.author Bryan, Allen Wayne en_US
dc.contributor.other Harvard University--MIT Division of Health Sciences and Technology. en_US
dc.date.accessioned 2010-04-28T17:11:50Z
dc.date.available 2010-04-28T17:11:50Z
dc.date.copyright 2009 en_US
dc.date.issued 2009 en_US
dc.identifier.uri http://hdl.handle.net/1721.1/54628
dc.description Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. en_US
dc.description Cataloged from PDF version of thesis. en_US
dc.description Includes bibliographical references (p. 123-133). en_US
dc.description.abstract Amyloids and prion proteins are clinically and biologically important beta-structures, whose supersecondary structures are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Recent work has indicated the utility of templates and pairwise probabilistic statistics in betastructure prediction. A new suite of programs, BETASCAN, STITCHER, and HELIXCAP, are presented to address the problem of amyloid structure prediction. BETASCAN calculates likelihood scores for potential beta-strands and strand-pairs based on correlations observed in parallel beta-sheets. The program then determines the strands and pairs with the greatest local likelihood for all of the sequence's potential beta-structures. BETASCAN suggests multiple alternate folding patterns and assigns relative ab initio probabilities based solely on amino acid sequence, probability tables, and pre-chosen parameters. STITCHER processes the output of BETASCAN and uses dynamic programming to 'stitch' structures from flexible abstract templates defined by constraints for amyloid-like all-beta structures. The 'stitched' structures are evaluated by a free-energy-based scoring algorithm incorporating BETASCAN scores, bonuses for favorable side-chain stacking, and penalties for linker entropy. The analyses of STITCHER structures emphasize the importance of side-chain stacking ladders in amyloid formation. HELIXCAP detects a class of end-caps, called beta-helix caps, which stabilize known beta-helix structures. These structures are known to stabilize globular beta-helix proteins and prevent their amyloidogenesis; their presence in a sequence is a powerful negative predictor of amyloid potential. Together, these algorithms permit detection and structural analysis of protein amyloidogenicity from sequence data, enhancing the experimental investigation of amyloids and prion proteins. en_US
dc.description.statementofresponsibility by Allen Wayne Bryan, Jr. en_US
dc.format.extent 139 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 http://dspace.mit.edu/handle/1721.1/7582 en_US
dc.subject Harvard University--MIT Division of Health Sciences and Technology. en_US
dc.title Prediction of parallel in-register amyloidogenic beta-structures In highly beta-rich protein sequences by pairwise propensity analysis en_US
dc.type Thesis en_US
dc.description.degree Ph.D. en_US
dc.contributor.department Harvard University--MIT Division of Health Sciences and Technology. en_US
dc.identifier.oclc 601927053 en_US


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