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.