Amyloid-beta42 oligomer structures from fibrils: a systematic molecular dynamics study.

Recent experimental data demonstrate that small, soluble amyloid-beta42 oligomers play an important role in Alzheimer's disease because they exhibit neurotoxic properties and also act as seed for fibril growth. We performed all-atom molecular dynamics simulations in explicit solvent of 0.7 micros in total on five Abeta9-42 oligomers (monomer through pentamer) starting from the fibril conformation. The initial conformation proves to be stable in the trimer to pentamer, and the two parallel in-register beta-sheets as well as the connecting turn are preserved. The dimer undergoes larger conformational changes in its C-terminus, and the predominant conformation detected exhibits an additional antiparallel beta-sheet in one of the subunits. This conformational rearrangement allows efficient shielding of hydrophobic residues from the solvent, which is not possible for a dimer in the fibril conformation. In addition to the presence of the hydrogen bonds in the beta-sheets, the larger oligomers are stabilized by interchain D23-K28 salt bridges, whereas a D23-N27 interaction is found in the dimer. The degree of structural similarity to the fibril conformation detected for the oligomers in the simulation may also offer a structural explanation for the experimental finding that trimers and tetramers act as more potent seeds in fibril formation than dimers because only small conformational changes will be required for fibril growth. The fact that the dimer predominantly exists in conformations distinct from the larger oligomers and the fibril is also interesting for the design of anti-Alzheimer drugs, because it suggests that multiple drugs might be required to target the structurally different neurotoxic oligomers.