Stabilities and conformations of Alzheimer's beta -amyloid peptide oligomers (Abeta 16-22, Abeta 16-35, and Abeta 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 beta-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 beta-peptide (Abeta) fragments 16-22, 16-35, and 10-35 (abbreviated Abeta(16-22), Abeta(16-35), and Abeta(10-35), respectively). Our simulations indicate that an antiparallel beta-sheet orientation is the most stable for the Abeta(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 Abeta(16-22) strands indicates a highly twisted fibril. Whereas the short Abeta(16-22) and Abeta(24-36) may exist in fully extended form, the linear parallel beta-sheets for Abeta(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 beta-sheets with higher stability. An intra-strand salt-bridge (D23-K28) stabilizes the bent hairpin-like hook structure. The bent double-beta-sheet model for the Abeta(10-35) similarly offers oligomer stability.
Ma
Buyong
B
Laboratory of Experimental and Computational Biology, and Intramural Research Support Program, Science Applications International Corporation, National Cancer Institute, Building 469, Room 151, Frederick, MD 21702, USA.
Nussinov
Ruth
R
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; C407125:amyloid beta-protein (10-35); C417223:amyloid beta-protein (16-22)