The assembly of proteins into amyloid fibrils is a complex process associated with more than 30 human diseases. Prefibrillar intermediates are believed to be the primary cytotoxic species in amyloid disease, yet little is known about these transient species at the molecular level. Our lab uses two-dimensional infrared (2D IR) spectroscopy to monitor the aggregation of amyloidogenic peptides and proteins in real time. We employ both isotopic labels and unnatural amino acids (UAAs) as site-specific vibrational probes to obtain detailed structural information throughout the aggregation process. In this talk, I will present our work with two amyloid systems. First, I will discuss how we are using 2D IR spectroscopy to determine the effect of metal and polymeric nanoparticles on the aggregation mechanism of human islet amyloid polypeptide. Second, I will discuss how the development of UAAs as spectroscopic probes enables us to move beyond the length limitations imposed by the need to make isotope-labeled peptides via solid-phase synthesis and study the aggregation of full-length α-synuclein. In both studies, we focus on identifying and characterizing transient oligomers with the goal of providing specific targets for inhibition.

Characterizing the aggregation of amyloid proteins with 2D infrared spectroscopy

ACS Spring Meeting 2021

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