Design and Synthesis of Macrocyclic Peptides for Studying the Supramolecular Assemblies of Beta-Sheets

This thesis describes my work in improving macrocyclic peptides as model systems used for studying beta-sheet assemblies. Chapter 1 details a strategy for synthesizing macrocyclic peptides bearing N-terminal substituents. This synthetic strategy was applied to a macrocyclic peptide with two natural sequences of amyloid-beta (Abeta) developed by Nowick group member Dr. Spencer. Two peptides with extended N-termini were synthesized and isolated, one with glycine as a proof-of-concept and one with glutamine to extend the natural sequence of Abeta.In Chapter 2, a system modeled from a macrocyclic peptide developed by former Nowick group member Dr. Khakshoor was explored. Part 1 describes the design of a pair of hetero-oligomeric peptides which take advantage of favorable aromatic interactions between phenylalanine and pentafluorophenylalanine. The formation of new aromatic interactions are observed, however these interactions are not as strong as predicted. In part 2, a sequential peptide design was performed, exploring which amino acids create a stable hydrophobic core to improve the oligomerization propensity and stability of Dr. Khakshoor's original model. It was determined that increasing the hydrophobicity at the N-terminus and in the aromatic core of the peptide increased the stability of the peptide oligomer by an order of magnitude