Towards Determining Amyloid Fibril Structures Using Experimental Constraints from Raman Spectroscopy

Using amylin(2029) as a model system, we demonstrate that experimental constraints measured by Raman spectroscopy can be used to determine the molecular structure of amyloid fibrils. We employ both polarized and non-polarized Raman spectroscopy measurements to determine the distributions of peptide backbone amide C=O and CN bond orientations, as well as Ramachandran ψ dihedral angles, adopted by amylin(20−29) fibrils. We then use these experimentally measured distributions as structural constraints to guide molecular dynamics (MD) simulations of an amylin(20−29) fibril structure. The resulting structure indicates that amylin(20−29) fibrils adopt a antiparallel β-sheet architecture in excellent agreement with previous studies. Overall, these results demonstrate that Raman spectroscopy provides the ability to determine the three-dimensional molecular structure of amyloid fibrils in a manner that complements gold standard techniques such as solid-state NMR.