Investigating the Effects of Stimuli on the Mechanisms of Polypeptide Aggregation and Assembly

Peptide-based self-assembling materials are promising for biomedical and advanced material applications due to their dynamic, tunable structures. Understanding the mechanisms driving peptide aggregation and self-assembly is crucial for rational design, particularly under the influence of external stimuli. The aggregation of human islet amyloid polypeptide (hIAPP) into fibrils plays a central role in Type II diabetes. This process involves the formation of intermediate structures that eventually organize into β-sheet-rich fibrils. Understanding how external stimuli, such as nanoparticles, influence this process is critical for identifying new ways to manage amyloid formation. Gold nanoparticles (AuNPs) are particularly interesting as modulators of peptide aggregation due to their ability to interact with peptides at specific residues. In this study, we focus on two residues within the FGAIL sequence of hIAPP: Phe23 (F23) and Ala25 (A25) – to study how AuNPs affect aggregation using ¹³C¹⁸O isotope labeling and two-dimensional infrared (2D IR) spectroscopy. The incorporation of isotope labels provides residue-specific resolution by separating the vibrational signals of labeled residues from the surrounding protein. The combination of frequency analysis and transition dipole strength (TDS) measurements provide a detailed understanding of local residue dynamics and global structural and can be applied more generally to most peptide aggregation or assembly processes. Preliminary findings show that, while 2D IR spectra of hIAPP aggregates appear similar with and without AuNPs, TDS spectra indicate that AuNPs promote the formation of more ordered structures. These results highlight the role of external stimuli in controlling peptide assembly and aggregation and offer new insights into peptide self-assembly, providing tools for the design of functional peptide-based materials with enhanced control over structural properties.