In silico study of full-length amyloid beta 1-42 tri- and penta-oligomers in solution.
Amyloid oligomers are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases including Alzheimer's disease. Using MD simulation techniques, we explored the contributions of the different structural elements of trimeric and pentameric full-length Abeta1-42 aggregates in solution to their stability and conformational dynamics. We found that our models are stable at a temperature of 310 K, and converge toward an interdigitated side-chain packing for intermolecular contacts within the two beta-sheet regions of the aggregates: beta1 (residues 18-26) and beta2 (residues 31-42). MD simulations reveal that the beta-strand twist is a characteristic element of Abeta-aggregates, permitting a compact, interdigitated packing of side chains from neighboring beta-sheets. The beta2 portion formed a tightly organized beta-helix, whereas the beta1 portion did not show such a firm structural organization, although it maintained its beta-sheet conformation. Our simulations indicate that the hydrophobic core comprising the beta2 portion of the aggregate is a crucial stabilizing element in the Abeta aggregation process. On the basis of these structure-stability findings, the beta2 portion emerges as an optimal target for further antiamyloid drug design.
Masman
Marcelo F
MF
Department of Molecular Neurobiology, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands. M.F.Masman@rug.nl
Eisel
Ulrich L M
UL
Csizmadia
Imre G
IG
Penke
Botond
B
Enriz
Ricardo D
RD
Marrink
Siewert Jan
SJ
Luiten
Paul G M
PG
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D003198:Computer Simulation; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D012996:Solutions; D013696:Temperature
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012996:Solutions; C075222:amyloid beta-protein (1-42)