UC Irvine

Aggregation of the islet amyloid polypeptide (IAPP) to form fibrils and oligomers is important in the progression of type 2 diabetes. This dissertation describes the effects of charge and hydrophobicity on the oligomerization of macrocyclic β-sheet peptides derived from IAPP. Incorporation of residues 11–17 of IAPP (RLANFLV) into a macrocyclic β-sheet peptide results in a monomeric peptide that does not self-assemble to form oligomers. Mutation of Arg11 to the uncharged isostere citrulline gives peptide homologues that assemble to form tetramers in both the crystal state and in aqueous solution (peptide 1Cit). The tetramers consist of hydrogen-bonded dimers that sandwich together through hydrophobic interactions. This dissertation also probes the role of charge and hydrophobicity by changing residue 11 to glutamic acid (peptide 1Glu) and leucine (peptide 1Leu). Diffusion ordered spectroscopy (DOSY) studies show that peptides 1Glu and 1Leu form tetramers in solution. NOESY studies confirm that both peptides formed the same sandwich-like tetramer as peptide 1Cit. 1H NMR spectroscopy at various concentrations reveal that peptide 1Leu has the highest propensity to form tetramers due to the leucine residue at

position 11 which contributes to packing. The effects of pH and charge on oligomerization are further probed by incorporation of histidine at position 11 (peptide 1His). DOSY studies show that peptide 1His forms a tetramer at high pH. At low pH, peptide 1His forms a new species that has not been observed by our group — a dimer. These studies demonstrate the importance of charge and hydrophobicity in the oligomerization of IAPP-derived peptides.