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