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Molecular Mechanism and Kinetics of Amyloid‑β42 Aggregate Formation: A Simulation Study
journal contribution
posted on 2019-11-08, 21:44 authored by Viet Hoang Man, Xibing He, Beihong Ji, Shuhan Liu, Xiang-Qun Xie, Junmei WangAs
an important neuropathological hallmark of Alzheimer’s
disease (AD), the oligomerization of amyloid-β (Aβ) peptides
has been intensively investigated in both theoretical and experimental
studies. However, the oligomerization space in terms of the kinetics,
molecular mechanism, and oligomer structures remains mysterious to
us. An equation that can quantitatively describe the time it takes
for Aβ oligomers to appear in the human brain at a given Aβ
monomer concentration is extremely vital for us to understand the
development and disease progression of AD. In this study, we utilized
molecular dynamics (MD) simulations to investigate the oligomerization
of Aβ42 peptides at five different monomer concentrations.
We have elucidated the formation pathways of Aβ tetramers, characterized
the oligomer structures, estimated the oligomerization time for Aβ
dimers, trimers, and tetramers, and for the first-time derived equations
that could quantitatively describe the relationship between the oligomerization
time and the monomer concentration. Applying these equations, our
prediction of oligomerization time agrees well with the experimental
and clinical findings, in spite of the limitations of our oligomerization
simulations. We have found that the Aβ oligomerization time
depends on the monomer concentration by a power of −2.4. The
newly established equations will enable us to quantitatively estimate
the risk score of AD, which is a function of age. Moreover, we have
identified the most dominant pathway of forming Aβ tetramers,
probably the most important and toxic Aβ oligomer. Our results
have shown that the structures of Aβ42 dimer, trimer,
and tetramer, which are distinguishable from each other, depend on
the monomer concentration at which the oligomers form. Representative
oligomer structures, which can serve as potential drug targets, have
been identified by clustering analysis. The MD sampling adequacy has
been validated by the excellent agreement between the calculated and
measured collisional cross section (CCS) parameters (the prediction
errors are within 2%). In a conclusion, this study provides the kinetics
and structure basis for developing inhibitors to decelerate the Aβ
oligomerization process.