Investigating the nanostructure and properties of Gly-X-Gly fibrils with aromatic central residues

Nichole Susan O'Neill

doi:10.17918/00001954

The research projects in this dissertation involve investigating tripeptides that can act as low molecular weight gelators. The Schweitzer-Stenner and Alvarez team have identified a novel class of peptides with the general motif Gly-X-Gly (X being a variable residue) that can aggregate and self-assemble into long fibrils, millimeters in length, which form dense sample spanning networks that underly very strong hydrogels. A subset of these peptides that are currently of high interest include Gly-His-Gly, Gly-Phe-Gly and Gly-Tyr-Gly, which all contain a central aromatic residue. The amide I' profiles of the vibrational spectra for these systems suggest sheet structures differing from canonical [beta]-sheets. A large portion of the work detailed here focuses on the investigation of the gelation process and structural properties of Gly-His-Gly and Gly-Phe-Gly fibrils. The IR/VCD experimental set-up is exploited to determine the main fibril axis of both Gly-His-Gly and Gly-Phe-Gly using a set of self-built algorithms which simulate the IR, VCD, and Raman amide I' band profiles. Simulations assignable to the delocalized amide I' modes were carried out by employing a classical Coupled Oscillator model that describes the coupling between excited eigenstates of harmonic oscillators. The peptide Gly-His-Gly is thought to be an idea candidate for adsorption of hydrophobic drugs due to its capability to form a fibril phase within a neutral pH range and the potential for [pi][pi]-interactions between imidazole side chains. The tunability of the Gly-His-Gly system's chemical and bulk properties have also been investigated using salts. A salt series varying in anions and cations have shown the kinetics and stability can be predicted using the Hofmeister series (a lyotropic series which orders ions according to their dissolving power with respects to protein and peptide solutes). It was hypothesized that gel stability could be predicted using ions associated with either low or high lyotropicity with the former increasing and the latter decreasing both aggregation and thermal stability. The rheology of the cation series supports this with chaotropes having lower melting temperatures compared to kosmotropes. UV-circular dichroism experiments revealed that salts at different ends of the cationic series reduce the thermal stability of the peptide fibrils to a similar extent. The final chapter focuses on current research aimed at drugs adsorption with Gly-His-Gly and Gly-Trp-Gly using ultra-performance liquid chromatography and UV-vis absorption spectroscopy.

Investigating the nanostructure and properties of Gly-X-Gly fibrils with aromatic central residues

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Investigating the nanostructure and properties of Gly-X-Gly fibrils with aromatic central residues

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