The discovery and characterization of biodegradable gels are important to many biomaterial applications. Low molecular weight peptides attracted increasing interest as gel forming compounds due to their low synthesis costs and the ease by which their reactive sites can be modified. Peptides are known to self-assemble into supramolecular structures, such as ribbons, nanotubes, and monolayers, which are predominantly composed of sheet-like structures. Several diseases are linked to the self-assembly of peptides/proteins including Alzheimer's disease, Parkinson's disease and Huntington's disease. Overall very little is understood regarding the self-assembly of peptides/proteins into fibrils. With respect to biotechnology, the self-assembly process has very positive aspects. It allows the generation of biocompatible material with incorporated biological function. Their biomedical and biotechnological relevance for developing suitable protocols for drug delivery, microfluidics, and tissue engineering/repair, is well established. This project will focus on elucidating specific interactions between peptides that lead to self-assembly and bulk gelation. Phase diagrams will be constructed to identify material constraints and identify potential applications for series of peptides. The results are expected to bring significant insight into designing new peptides with tailored or controlled aggregation kinetics and gelation properties for a broad range of applications. The project outcomes will have significant impact in understanding and interpreting the role of peptides and their sequence in disease manifestation. Lastly, the project will result in the training of graduate and undergraduate students in the fields of Chemistry, Chemical Engineering, and Physics.
This research project is motivated by the discovery of the unexpected gelation of cationic glycylalanylglycine (GAG) in ethanol/water and glycylhistidylglycine (GHG) in water at neutral pH. The planned experiments and computations are aimed at a thorough assessment of the molecular mechanisms and microscopic and macroscopic properties of gels formed by the above unblocked GxG peptides. We will focus initially on five tripeptides: GAG, GHG, GVG, GDG and GFG and their respective blocked derivatives. Experimental investigations will determine the effect of environment (solvent composition, pH, temperature, peptide concentration) on peptide conformation and interaction energies. Rheology will be used to determine the strength, compliance, and recovery of volume spanning networks. Circular dichroism (CD), IR, vibrational spectroscopy, and rheology will be used to construct phase diagrams with regard to temperature, peptide concentration, pH and the mole fraction of co-solvents. The phase diagrams will also be analyzed in the context of current theories of gelation to determine interaction energies. Finally, investigations will focus on exploring the different steps of the tripeptide gelation process: from the onset of tripeptide aggregation to the formation of large scale fibrils. Some key questions that will be answered are how the peptides are integrated into a sample spanning network and what type of structure and conformation do the peptides make inside fibrils. A strong emphasis will be placed on characterizing the kinetics of gelation and the dependence of kinetic rates on external stimuli. Furthermore, we will determine the local conformation of peptides in the crystalline fibrils by combining vibrational spectroscopy data with molecular dynamics and density functional calculations. The unique comparison and analysis of simultaneous rheological, computational and spectroscopic data will unfold the complexities of peptide aggregation, fibrillization, and ultimately network formation from the molecular to macroscopic scale. The proposed research is clearly at the interface between physics, chemistry and biology. The project would provide funding for graduate students and one undergraduate student. Graduate and undergraduate students will be trained on a variety of instruments and learn how to combine rather different data sets into a common picture describing the investigated systems. Undergraduate research will be become part of the student's Co-op experience.
