Towards Determining Amyloid Fibril Structures Using Experimental Constraints from Raman Spectroscopy

We present structural models for three different amyloid fibril polymorphs prepared from amylin20−29 (sequence SNNFGAILSS) and amyloid-β25−35 (Aβ25−35) (sequence GSNKGAIIGLM) peptides. These models are based on amide C=O bond and Ramachandran ψ-dihedral angle data from Raman spectroscopy, which were used structural constraintsto guide molecular dynamics (MD) simulations. The resulting structural models indicate that the basic structural motif of amylin20−29 and Aβ25−35 fibrils are extended β-strands. Our data indicates that amylin20−29 forms both antiparallel and parallel β-sheet fibril polymorphs, while Aβ25−35 forms a parallel β-sheet fibril structure. Overall, our work lays the foundation for using Raman spectroscopy in conjunction with MD simulations to determine detailed molecular-level structural models of amyloid fibrils in a manner that complements gold-standard techniques such as solid-state NMR and cryogenic electron microscopy.