Structure and Physicochemical Properties of the Aβ42 Tetramer: Multiscale Molecular Dynamics Simulations

Despite
years of intensive research, little is known about oligomeric
structures present during Alzheimer’s disease (AD). Excess
of amyloid beta (Aβ) peptides and their aggregation are the
basis of the amyloid cascade hypothesis, which attempts to explain
the causes of AD. Because of the intrinsically disordered nature of
Aβ monomers and the high aggregation rate of oligomers, their
structures are almost impossible to resolve using experimental methods.
For this reason, we used a physics-based coarse-grained force field
to extensively search for the conformational space of the Aβ42
tetramer, which is believed to be the smallest stable Aβ oligomer
and the most toxic one. The resulting structures were subsequently
optimized, tested for stability, and compared with the proposed experimental
fibril models, using molecular dynamics simulations in two popular
all-atom force fields. Our results show that the Aβ42 tetramer
can form polymorphic stable structures, which may explain different
pathways of Aβ aggregation. The models obtained comprise the
outer and core chains and, therefore, are significantly different
from the structure of mature fibrils. We found that interaction with
water is the reason why the tetramer is more compact and less dry
inside than fibrils. Physicochemical properties of the proposed all-atom
structures are consistent with the available experimental observations
and theoretical expectations. Therefore, we provide possible models
for further study and design of higher order oligomers.