Label‐Free Detection of π‐Stacking Interactions During Tryptophan Self‐Assembling Into Amyloid‐Like Structures Using Surface‐Enhanced Raman Scattering

ABSTRACT The formation of amyloid fibrils by different proteins and peptides is a well‐studied topic. In the last decade, it has been reported that metabolites can also self‐assemble into amyloid‐like fibrils. The aggregation of single amino acids such as phenylalanine, tyrosine, and tryptophan has also been linked to tyrosinemia type II, hypertryptophanemia, and Hartnup diseases. It is a challenge to monitor the intermolecular interactions involved in the supramolecular self‐assembling of metabolites in a time‐dependent manner. Here, the surface‐enhanced Raman scattering (SERS) technique was used to directly probe the changes in the molecular interactions during the self‐assembling of tryptophan into amyloid‐like structures, particularly in the initial stages. We showed that this simple and label‐free nanoplasmonic‐based methodology can be used to examine at the molecular level the formation of amyloid‐like aggregates as a function of time. Specifically, the technique was shown to be sensitive and provide insights into the formation of hydrogen bonding, π‐stacking interactions, and hydrophobicity changes during the self‐assembling of tryptophan. Thus, this work can open new possibilities for the applications of SERS to describe in more detail the mechanisms of formation of other metabolites assembled structures, which may be valuable for understanding several related diseases.