Structural Variations in the Cross-β Core of Amyloid β Fibrils Revealed by Deep UV Resonance Raman Spectroscopy

Understanding fibrillogenesis at a molecular level requires detailed structural characterization of amyloid fibrils. The combination of deep UV resonance Raman (DUVRR) spectroscopy and post mortem hydrogen-deuterium exchange (HX) was utilized for probing parallel vs antiparallel beta-sheets in fibrils prepared from full-length A beta(1-40) and A beta(34-42) peptides, respectively. Using previously published structural data based on solid-state NMR analysis, we verified the applicability of Asher's approach for the quantitative characterization of peptide conformation in the A beta(1-40) fibril core. We found that the conformation of the parallel beta-sheet in the A beta(1-40) fibril core is atypical for globular proteins, while in contrast, the antiparallel beta-sheet in A beta(32-42) fibrils is a common structure in globular proteins. In contrast to the case for globular proteins, the conformations of parallel and antiparallel beta-sheets in A beta fibril cores are substantially different, and their differences can be distinguished by DUVRR spectroscopy.