Stabilities and conformations of Alzheimer ’ s - amyloid peptide oligomers ( A 16 22 , A 16 – 35 , and A 10 35 ) : Sequence effects

Previously, we have studied the minimal oligomer size of an aggregate amyloid seed and the mechanism of seed growth with a multilayer -sheet model. Under high temperature simulation conditions, our approach can test the stability of possible amyloid forms. Here, we report our study of oligomers of Alzheimer’s amyloid -peptide (A ) fragments 16–22, 16–35, and 10–35 (abbreviated A 16–22, A 16–35, and A 10–35, respectively). Our simulations indicate that an antiparallel -sheet orientation is the most stable for the A 16–22, in agreement with a solid state NMR-based model [Balbach, J. J., Ishii, Y., Antzutkin, O. N., Leapman, R. D., Rizzo, N. W., et al. (2000) Biochemistry 39, 13748–13759]. A model with twenty-four A 16–22 strands indicates a highly twisted fibril. Whereas the short A 16–22 and A 24–36 may exist in fully extended form, the linear parallel -sheets for A 16–35 appear impossible, mainly because of the polar region in the middle of the 16–35 sequence. However, a bent double-layered hairpin-like structure (called hook) with the polar region at the turn forms parallel -sheets with higher stability. An intra-strand salt-bridge (D23K28) stabilizes the bent hairpin-like hook structure. The bent double-sheet model for the A 10–35 similarly offers oligomer stability.