Anders Irbäck

Small soluble oligomers, as well as dimers in particular, of the amyloid β-peptide (Aβ) are believed to play an important pathological role in Alzheimer's disease. Here, we investigate the spontaneous dimerization of Aβ42, with 42 residues, by implicit solvent all-atom Monte Carlo simulations, for the wild-type peptide and the mutants F20E, E22G and E22G/I31E. The observed dimers of these variants share many overall conformational characteristics but differ in several aspects at a detailed level. In all four cases, the most common type of secondary structure is intramolecular antiparallel β-sheets. Parallel, in-register β-sheet structure, as in models for Aβ fibrils, is rare. The primary force driving the formation of dimers is hydrophobic attraction. The conformational differences that we do see involve turns centered in the 20-30 region. The probability of finding turns centered in the 25-30 region, where there is a loop in Aβ fibrils, is found to increase upon dimerization and to correlate with experimentally measured rates of fibril formation for the different Aβ42 variants. Our findings hint at reorganization of this part of the molecule as a potentially critical step in Aβ aggregation.