Abstract:
Alzheimer’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.
