Insight into the principles of amphipathic peptide self-assembly.

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2012. Chapter 1 coauthored with Bradley L. Nilsson. The work presented in Chapter 2 is coauthored with Derek M. Ryan and David A. Nissan. The work presented in Chapter 3 is coauthored with Wathsala Liyanage and Alexander J. Federation.Amyloid is associated with protein pathologies such as Alzheimer's disease, Parkinson's Disease, Spongiform Encephalopthies (Mad Cow's Disease), as well as Type II Diabetes. In recent years, non-pathogenic functional amyloids that are conserved in normal biological processes have been identified. Short amphipathic peptides have also been designed for the development of amyloid-inspired biomaterials. Amphipathic peptide self-assembled materials have been exploited in the development of multivalent immunostimulants, drug delivery/gene transfection vectors, and matrices for cell and tissue growth ex vivo. Despite these impressive advancements, there remain considerable gaps in our understanding of the relationship between peptide sequence, self-assembly propensity, and the resulting fibril and hydrogel properties. Insight into the principles that govern the self-assembly and hydrogelation of amphipathic peptides will facilitate the design of amyloidinspired materials with predictable structures, properties and functions. This thesis investigates the role of aromatic π-π and hydrophobic noncovalent interactions in the self-assembly and hydrogelation of amphipathic peptides with the general sequence Ac-(XZXZ)2-NH2. Self-assembly propensity was found to be generally dependent on peptide hydrophobicity. Although not critical for β-sheet fibril formation, aromatic π-π interactions influenced the formation of unique helical tape morphologies. It was also demonstrated that hydrogel rigidity correlated to the presence of aromatic amino acids. These findings contribute insight into the basic principles that promote self-assembly and hydrogelation of amphipathic β-sheet peptides. The design of functional stimulus-responsive biomaterials is increasingly important. In this thesis we also designed a peptide that could be cyclized through a reversible disulfide bond. A reduction-sensitive trigger has the potential to target the intracellular space of cells that tends to be reducing, while the extracellular space is generally oxidizing. In the cyclic form, β-sheet conformation and self-assembly were inhibited. Self-assembly and hydrogelation can be triggered by addition of chemical reductants to the cyclic peptide solution. This work demonstrated that conformational constraint is a viable trigger to control amphipathic peptide self-assembly and hydrogelation