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dc.contributorHamilton, Darrenen_US
dc.contributorvan Giessen, Alanen_US
dc.contributorGillis, Garyen_US
dc.contributor.advisorDecatur, Seanen_US
dc.contributor.authorPothier, Lauraen_US
dc.date.accessioned2011-02-16T13:47:28Z
dc.date.available2011-02-16T13:47:28Z
dc.date.issued2011-02-16
dc.date.submitted2007-05-16 15:06:27en_US
dc.identifier.urihttp://hdl.handle.net/10166/772
dc.description.abstractAggregation of proteins into amyloid fibers is associated with a number of diseases, including Alzheimer s, the spongiform encephalopathies, and type II diabetes. The mechanism of polypeptide aggregation and the relationship between peptide sequence and amyloid structure are still largely unanswered questions. One approach to study these problems is the characterization of amyloids formed by model peptides; small polypeptides are accessible both to a wide range of experimental biophysical characterization and molecular dynamics simulations. An example of a well-studied model peptide system is A-Beta 16-22 (KLVFFAE), derived from a central portion of the A-Beta polypeptide, a 40-to-42 residue polypeptide associated with Alzheimer s disease. Both molecular dynamics simulations [42] and FTIR studies [10] have found that this sequence forms in-register, antiparallel Beta-sheets when isolated from the full peptide, possibly in part due to salt bridges formed between the oppositely charged residues at either end of the strand in neutral pH. Many amyloids associated with longer polypeptides, such as full length A-Beta systems, contain parallel beta-sheets [18, 19]. It would be advantageous to identify features in polypeptide sequences that determine the orientation of strands within beta-sheet aggregates. In a recently published analysis of residue frequency within beta-sheets found in proteins within the protein data bank, asparagine has a particularly high propensity for parallel beta-sheets. This effect may be due to interstrand hydrogen bond formation between asparagine side chains within an in register parallel beta sheet. However, the side chain structure of asparagine differs from that of glutamine by only one alkyl group, yet glutamine does not have the same propensity [15]. In this study, we used the well-characterized A-Beta 16-22 peptide as a system for exploring the effects of asparagine and glutamine substitutions on beta sheet formation. We have prepared a series of derivatives of A-Beta 16-22 with single-side substitutions of either asparagine or glutamine. The conformation and thermostability of the aggregates formed by these peptides have been characterized by variable-temperature FTIR. In addition, for two of the sequences, we have carried out 5 ns simulations of parallel dimers mutated at position 17 in implicit solvent.en_US
dc.description.sponsorshipChemistryen_US
dc.language.isoen_USen_US
dc.titleEffects of Amino Acid Substitutions on the Conformation and Stability of A-Beta (16-22) Aggregatesen_US
dc.typeThesisen_US
dc.date.gradyear2007en_US
mhc.institutionMount Holyoke Collegeen_US
mhc.degreeUndergraduateen_US
dc.rights.restrictedpublic


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