Figure 4 : Proposed structures that explain the different IR spectra and AFM images for low- versus high-salt fibrils.

From: Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy

Figure 4

By adding ions to the solution of αS monomers the conformational equilibrium is changed from a situation where most αS molecules are in a conformation in which the oppositely charged C- and N-terminus shield the hydrophobic NAC region, to a situation in which the charge interaction is screened due to the ions6,13,14,16,17. This leads to a more exposed NAC region, in which αS can transiently adopt intramolecular β-sheet structure15, with a potential high fibrillization propensity after a 90° rotation of the hydrogen bonds that has been observed before in aggregating proteins69. The width of the low-salt fibrils, as observed with AFM, is similar to the length of an extended αS monomer, and the low-frequency shoulder (~1617 cm−1) in the IR spectra is only observed for a parallel orientation of hydrogen-bonded β-sheets. We therefore hypothesize that in a low-salt buffer the C- and N-terminus shielded monomer conformation is in equilibrium with an extended conformation that has a stronger fibrillization propensity than the shielded conformation (albeit much less strong as compared to the intramolecular β-sheet conformation that is populated in a high-salt buffer, as judged from the much slower aggregation rate of low-salt fibrils). The extended monomer conformation leads to an extended and parallel fibril structure. This hypothesis also explains the fact that the low-salt fibrils exhibit no twist, whilst the high-salt fibrils are composed of two entwined twisting protofibrils (as also observed with cryo-electron microscopy83), as both charge84 and size85 are known to influence the twisting properties of protofibrils.