Size-Dependent Conformational Features of Aβ<sub>17–42</sub> Protofilaments from Molecular Simulation Studies
2017-08-30T00:00:00Z (GMT) by
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 Aβ<sub>17–42</sub> protofilaments, namely, O<sub>5</sub> (pentamer), O<sub>8</sub> (octamer), O<sub>10</sub> (decamer), O<sub>12</sub> (dodecamer), and O<sub>14</sub> (tetradecamer). Analysis of the free energy profiles of the aggregates showed that the higher order protofilaments (O<sub>10</sub>, O<sub>12</sub>, and O<sub>14</sub>) undergo conformational transitions between two minimum energy states separated by small energy barriers, while the smaller aggregates (O<sub>5</sub> and O<sub>8</sub>) remain in single deep minima surrounded by high barriers. Importantly, it is demonstrated that O<sub>10</sub> 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 (O<sub>10</sub> 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.