ci7b00407_si_001.pdf (824.98 kB)
Size-Dependent Conformational Features of Aβ17–42 Protofilaments from Molecular Simulation Studies
journal contribution
posted on 2017-08-30, 00:00 authored by Prabir Khatua, Sudipta Kumar Sinha, Sanjoy BandyopadhyayAlzheimer’s disease is caused
due to aggregation of amyloid
beta (Aβ) peptide into soluble oligomers and insoluble fibrils
in the brain. In this study, we have performed room temperature molecular
dynamics simulations to probe the size-dependent conformational features
and thermodynamic stabilities of five Aβ17–42 protofilaments, namely, O5 (pentamer), O8 (octamer),
O10 (decamer), O12 (dodecamer), and O14 (tetradecamer). Analysis of the free energy profiles of the aggregates
showed that the higher order protofilaments (O10, O12, and O14) undergo conformational transitions
between two minimum energy states separated by small energy barriers,
while the smaller aggregates (O5 and O8) remain
in single deep minima surrounded by high barriers. Importantly, it
is demonstrated that O10 is the crossover point for which
the twisting of the protofilament is maximum, beyond which the monomers
tend to rearrange themselves in an intermediate state and eventually
transform into more stable conformations. Our results suggest that
the addition of monomers along the axis of an existing protofilament
with a critical size (O10 according to the present study)
proceeds via an intermediate step with relatively less stable twisted
structure that allows the additional monomers to bind and form stable
larger protofilaments with minor rearrangements among themselves.
More importantly, it is demonstrated that a combination of twist angle
and end-to-end distance can be used as a suitable reaction coordinate
to describe the growth mechanism of Aβ protofilaments in simulation
studies.