Analysis of the stabilities of hexameric amyloid-β(1-42) models using discrete molecular dynamics simulations.

Amyloid-β (Aβ) oligomers appear to play a pivotal role in Alzheimer's disease. A 42 residue long alloform, Aβ42, is closely related to etiology of the disease. In vitro results show evidences of hexamers; however structures of these hexamers have not been resolved experimentally. Here, we use discrete molecular dynamics (DMD) to analyze long duration stabilities of Aβ42 hexamer models developed previously in our lab. The hydrophobic core of these models is a six-stranded β-barrel with 3-fold radial symmetry formed by residues 30-40. This core is shielded from water by residues 1-28. The nine models we analyzed differ by the relative positions of the core β-strands, and whether the other segments surrounding the core contain α helices or β-strands. A model of an annular protofibril composed of 36 Aβ peptides was also simulated. Results of these model simulations were compared with results of aggregation simulations that started from six well separated random coils of Aβ42 and with simulations of two known β-barrel structures. These results can be categorized into three groups: stable models with properties similar or superior to those of experimentally determined β-barrel proteins, aggregation-prone models, and an amorphous aggregate from random coils. Conformations at the end of the simulation for aggregation-prone models have exposed hydrophobic core with dangling β-strands on the surface. Hydrogen bond patterns within the β-barrel were a critical factor for stability of the β-barrel models. Aggregation-prone conformations imply that the association of these hexamers may be possible, which could lead to the formation of larger assemblies.