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    NMR characterization guides the design of beta hairpins and sheets while providing insights into folding cooperativity and dynamics

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    Date
    2006
    Author
    Hudson, Frederick Michael Lewis
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    Abstract
    Peptides populating the beta hairpin and sheet folding motifs commonly found in proteins have been designed using peptide design criteria and these sequences have been characterized with NMR spectroscopy. The use of chemical shift deviations (CSDs are obtained by subtracting random coil reference chemical shifts from observed shifts) of backbone protons (Halpha and HN) is shown to be of significant value for the determination of the fold populations of these structures, as well as providing information allowing for detailed structural analysis. For beta hairpin systems, detailed structural analysis led to multiple important findings: (1) strand alignment in hairpins is driven towards the most energetically favorable association of the strands which results in similar strand alignment regardless of loop length and turn type; (2) when strands are joined with loops of various lengths, hairpin folds are favored with particular loop lengths; and (3) turn types have characteristic CSD patterns which can be used for their identification. When the CSD technique was applied for the characterization of a 3-stranded sheet (double hairpin), determination of the relative stability of two-residue turn forming sequences was possible. Measurement of the fold propensity of individual hairpins within three-stranded sheet sequences allowed for a determination of the cooperativity of the folding of the sheet sequences using a strict four-state model which provided larger estimates of cooperativity than had been previously reported using two-state analyses. At this point, the development of a new technique in this laboratory for measuring the folding and unfolding rates of peptides using an NMR line-broadening analysis, allowed for the measurement of these rates for a hairpin system in an isolated context and when folding in a three-stranded sheet. These rate measurements further suggest that a four-state model is appropriate for the description of the behavior of these sequences.
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    http://hdl.handle.net/1773/8639
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    • Chemistry [339]

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