posted on 2017-10-11, 00:00authored byYang Cao, Xuehan Jiang, Wei Han
Early oligomerization during amyloid-β
(Aβ) aggregation
is essential for Aβ neurotoxicity. Understanding how unstructured
Aβs assemble into oligomers, especially those rich in β-sheets,
is essential but remains challenging as the assembly process is too
transient for experimental characterization and too slow for molecular
dynamics simulations. So far, atomic simulations are limited only
to studies of either oligomer structures or assembly pathways for
short Aβ segments. To overcome the computational challenge,
we combine in this study a hybrid-resolution model and adaptive sampling
techniques to perform over 2.7 ms of simulations of formation of full-length
Aβ40 dimers that are the earliest toxic oligomeric species.
The Markov state model is further employed to characterize the transition
pathways and associated kinetics. Our results show that for two major
forms of β-sheet-rich structures reported experimentally, the
corresponding assembly mechanisms are markedly different. Hairpin-containing
structures are formed by direct binding of soluble Aβ in β-hairpin-like
conformations. Formation of parallel, in-register structures resembling
fibrils occurs ∼100-fold more slowly and involves a rapid encounter
of Aβ in arbitrary conformations followed by a slow structural
conversion. The structural conversion proceeds via diverse pathways
but always requires transient unfolding of encounter complexes. We
find that the transition kinetics could be affected differently by
intra-/intermolecular interactions involving individual residues in
a conformation-dependent manner. In particular, the interactions involving
Aβ’s N-terminal part promote the assembly into hairpin-containing
structures but delay the formation of fibril-like structures, thus
explaining puzzling observations reported previously regarding the
roles of this region in the early assembly process.