1.Introduction
Amyloid-beta (Aβ) peptides of 40 and 42 amino acids are proteolytically
cleaved form amyloid precursor protein by β- and γ-secretases. Soluble
Aβ dimers isolated from Alzheimer’s cortex directly induce tau
hyperphosphorylation and neuritic degeneration, and small Aβ oligomers
are believed to the most toxic species.1,2 The
aggregation kinetics of Aβ follows a sigmoidal curve with three phases:
a lag phase free of any Thioflavin T fluorescence signal, a growth phase
or fibril elongation followed by a saturation
phase.3,4 Aβ42, less abundant but more toxic than in
its Aβ40 counterpart, is very sensitive to protein concentration upon
aggregation in the bulk solution, and also pH, temperature, the presence
of membrane and the addition of seeds. Characterizing the early Aβ
oligomers is challenging experimentally and
computationally.5-7
This is an experimental challenge due to the transient and heterogeneous
ensemble of oligomer structures, the fact that most experimental
observables provide time- and space-averaged
properties,6 and the µs time resolution cannot be
achieved yet.8 This is a challenge for computer
simulations due to the accuracy of the protein and water force
fields,9,10 and the time scale of primary nucleation
in pure buffer which is on the order of several hours for Aβ42 at µM
concentrations.4 By using atomistic molecular dynamics
(MD) simulations, the current time lengths vary from 2.5 to 30 µs for 20
Aβ42 peptides with an implicit solvent model,11 and
Aβ40 monomer in explicit water,12 respectively.
Simulations of Aβ40/42 species with free lipids and calcium ions in
aqueous solution are also currently limited to the µs time
scale.13-15 Going beyond this time scale or sampling
rare events has been made possible by the use of coarse-grained or
mesoscopic models and enhanced sampling techniques such as path or
umbrella sampling and metadynamics, among others. Our current structural
view of Aβ40/42 monomers and small oligomers is random coil, with
increasing β-sheet content as the oligomer size
increases.16 In this study, we emphasize other
metastable oligomers based on α-helix bundles that are predicted by the
AlphaFold2 machine learning and are indirectly supported by
low-resolution experimental data on many amyloid polypeptides.