2.2 Random Coil Oligomers with β-sheet content
While small α-helix and β-strand contents are present in the spectrum of conformations of Aβ42, our current conformational view for small Aβ42 oligomers is funneled toward β-sheet conformations for several reasons.
The first reason comes from the high propensity of β-sheets revealed by oligomer simulations at a very high concentration of small fragments of Aβ (Aβ16-22, Aβ37-42, Aβ25-35, Aβ10-24 and Aβ35-40), tau (PHF6 motif, repeats R1-R4), transthyretin (105-115) and β2-microglobulin (83-89) peptides which also form fibrils.29-36 It is notable, however, that two simulations on Aβ16-22 oligomers proposed helical intermediates.37-39
Second, the preference for β-sheet formation comes from the fact that many computational methods do not explore the full conformational ensemble. On-lattice Monte Carlo simulations do not allow the formation of α-helix oligomers40-42 and atomistic metadynamics simulations do not include collective variables associated with side chain packings of α-rich oligomers. It is important to note that the introduction of the steric zipper interface between the side chains as a collective variable was found critical in metadynamics simulations to understand the primary nucleation of 18 Aβ37-42 peptides.35
Additionally, off-lattice simplified models aimed at understanding primary and second nucleation mechanisms either tune the probability of the β-strand monomer,43 or consider three states for Aβ dimers with coil-coil, coil-β, and β-β character to explain the transition from amorphous to fibrils.44 These models suggest that fibril formation at a concentration of mM can occur through the assembly of early ordered oligomers, the assembly of nonfibrillar aggregates rich in β-sheet content, or the formation of amorphous aggregates which reorganize to β-sheet aggregates and to fibrils.
Beta-rich Aβ42 oligomers ranging from elongated to compact shapes were described by ss-NMR spectroscopy, ion mobility separation coupled to mass spectrometry, and simulations, featuring multiple interfaces, mixed parallel/antiparallel strands, perpendicular β-sheets and β-barrels.6,7,11,28,45-49 For instance, atomistic simulations in explicit solvent revealed β-barrel motifs in Aβ42 trimer and tetramer.48,50,51 An hexamer peptide barrel was found experimentally to be the building block of Aβ protofibrils.52
Finally, using the multimer version of AlphaFold2,53we found that Aβ42 dimers up to hexamers have a non-negligible probability to display intramolecular β-hairpin conformations spanning the CHC and the C-terminus (residues 30-42), and in some cases to form β-barrels.54