Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2020.
The first part of this thesis (Chapter 2) describes a kinetic analysis comparing peptide assembly into pleated versus rippled β-sheets. The first experimental example of rippled β-sheets was reported in 2011 despite predictions by Pauling and Corey in 1953. Rippled β-sheets are a two-component structure formed by coassembly of an equimolar mixture of enantiomeric peptides, resulting in arrangement of alternating L/D strands within the β-sheet. There is still much that is not understood about rippled β-sheets in comparison to the properties and structure of pleated β-sheets. Previous studies have found a thermodynamic advantage for forming rippled β-sheets, but without structural information or an idea of the energetic landscape, it is unclear why this is the case. The purpose of the work described in Chapter 2 is to find if there is a kinetic preference for rippled β-sheets over pleated β-sheets.
The second part of this thesis (Capters 3 and 4) describes the application of these peptides as a novel cell-penetrating peptide delivery vector. The work in Chapter 3 details initial design and proof-of-concept of disulfide constrained cyclic amphipathic peptides (dcCAPs) for delivery of siRNA both in vitro and in vivo. dcCAPs are able to condense with siRNA to form nanoparticles. Chapter 4 contains efforts to elucidate the mechanism of cellular internalization and gain an understanding of the structural basis for dcCAP-siRNA binding. Understanding interactions between dcCAP and siRNA during nanoparticle formation as well as interactions between the dcCAP-siRNA nanoparticle and the cell membrane will allow us to design an idealized siRNA carrier.
