We propose to use peptide model systems to elucidate the origins of beta-sheet conformational stability. This effort will take advantage of recent advances from our laboratory and from others that have identified a general strategy for inducing small peptides to adopt antiparallel beta-sheet conformations in aqueous solution. This approach focuses on the beta-hairpin folding unit, in which two strands are connected by a short loop. We will use hairpin-based experimental designs to achieve four specific aims. (1) We will use model systems to probe antiparallel beta-sheet secondary structure, including the contributions of cooperativity and interstrand sidechain-sidechain interactions to conformational stability. (2) We will examine the origins of parallel beta-sheet stability with model systems developed by extention from our antiparallel beta-sheet work and from results of other workers. (3) We will build from our beta-sheet secondary structure models to create a new tertiary structural motif, in which a polyproline II (PPII) helix packs against one face of a two-stranded beta-sheet. This motif is likely to display high conformational stability with relatively few residues. The proposed betabetaPPII motif will provide a unique opportunity to determine the origins of cooperativity at the tertiary structure level. (4) We will use the hairpin architecture to evaluate interactions between peptide strands and non-peptide oligomers. Ultimately, we would like to identify unnatural oligomers that can bind in beta-sheet-like fashion to an extended peptide strand, and thereby disrupt deleterious protein aggregation processes. The proposed beta-sheet model studies will enhance our understanding of protein folding preferences by providing a complement to the extensive alpha-helix model studies that have been reported from many laboratories. Our results should also contribute to protein design and engineering efforts, and to the development of chemotherapies for amyloid diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Wehrle, Janna P
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University of Wisconsin Madison
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Mortenson, David E; Kreitler, Dale F; Thomas, Nicole C et al. (2018) Evaluation of ?-Amino Acid Replacements in Protein Loops: Effects on Conformational Stability and Structure. Chembiochem 19:604-612
Eddinger, Geoffrey A; Gellman, Samuel H (2018) Differential Effects of ?3 - versus ?2 -Amino Acid Residues on the Helicity and Recognition Properties of Bim BH3-Derived ?/?-Peptides. Angew Chem Int Ed Engl 57:13829-13832
Thomas, Nicole C; Bartlett, Gail J; Woolfson, Derek N et al. (2017) Toward a Soluble Model System for the Amyloid State. J Am Chem Soc 139:16434-16437
Kreitler, Dale F; Mortenson, David E; Forest, Katrina T et al. (2016) Effects of Single ?-to-? Residue Replacements on Structure and Stability in a Small Protein: Insights from Quasiracemic Crystallization. J Am Chem Soc 138:6498-505
Hayouka, Zvi; Thomas, Nicole C; Mortenson, David E et al. (2015) Quasiracemate Crystal Structures of Magainin 2 Derivatives Support the Functional Significance of the Phenylalanine Zipper Motif. J Am Chem Soc 137:11884-7
Kung, Vanessa M; Cornilescu, Gabriel; Gellman, Samuel H (2015) Impact of Strand Number on Parallel ?-Sheet Stability. Angew Chem Int Ed Engl 54:14336-9
Mortenson, David E; Steinkruger, Jay D; Kreitler, Dale F et al. (2015) High-resolution structures of a heterochiral coiled coil. Proc Natl Acad Sci U S A 112:13144-9
Fu, Li; Wang, Zhuguang; Psciuk, Brian T et al. (2015) Characterization of Parallel ?-Sheets at Interfaces by Chiral Sum Frequency Generation Spectroscopy. J Phys Chem Lett 6:1310-5
Laaser, Jennifer E; Skoff, David R; Ho, Jia-Jung et al. (2014) Two-dimensional sum-frequency generation reveals structure and dynamics of a surface-bound peptide. J Am Chem Soc 136:956-62
Maynard, Stacy J; Almeida, Aaron M; Yoshimi, Yasuharu et al. (2014) New charge-bearing amino acid residues that promote ?-sheet secondary structure. J Am Chem Soc 136:16683-8

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