| The overarching theme of the work presented in this dissertation is the design of peptides of less than 30 residues in length that adopt conformations found in proteins in order to further our understanding of such structures. There is an additional focus on creating very stable peptides or using hyperstable peptides in novel ways to understand and invent new constructs that can be used as biological tools. Circular Dichroism and 1H NMR through Chemical Shift Deviations are used to characterize a number of designed peptides and peptidomimetics including antiparallel beta-hairpins, parallel beta-hairpins and TrpCage miniproteins. Optimization and minimization of a designed antiparallel beta-hairpin was completed to investigate the limit of a stabilizing turn flanking Trp/Trp interaction to induce structure in short peptides, and answer questions regarding the geometry of Trp/Trp and other aromatic/aromatic interactions. The potential of capping motifs to stabilize antiparallel beta-hairpins was also considered; until very recently capping interactions were applied only to alpha-helices, and our investigation involves one of the first explorations of C-terminal side-chain effects on a beta-hairpin construct. In addition an alternative beta-cap was used to stabilize beta-hairpins with long flexible loops. While designed antiparallel hairpins have provided a considerable amount of information regarding beta-sheet folding, the lack of parallel counterparts has left a gap in our knowledge. Attempts are made in the design of parallel beta-hairpins to further our understanding of parallel beta-sheet structure. The TrpCage miniprotein was investigated as a potential scaffold for the design of peptidomimetic, multidomain miniproteins. These model systems have added to our overall understanding of protein folding and many of the peptides presented are highly stable. The development of such peptides that adopt highly populated conformations has prompted numerous studies that apply such systems as therapeutics and biomaterials. |
