Model peptides for Binding Studies on peptide-peptide Interactions: The Case of Amyloid beta (1-42) Aggregates

M.F.MASMAN, U. M. EISEL, I. CSIZMADIA, B. VISKOLZ, R.D.ENRIZ, B. PENKE, P. G.M. LUITE

JOURNAL OF PHYSICAL CHEMISTRY B

Am. Chem Soc

Lugar: Washington; Año: 2009 vol. 113 p. 11710 - 11719

1089-5647

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 A
1-42 aggregates in solution to their stability and conformational dynamics. We found that our models are stable at a temperature of 310 K, andconverge toward an interdigitated side-chain packing for intermolecular contacts within the two
-sheet regions of the aggregates:
1 (residues 18-26) and
2 (residues 31-42). MD simulations reveal that the
-strand twist is a characteristic element of A
-aggregates, permitting a compact, interdigitated packing of side chains from neighboring
-sheets. The
2 portion formed a tightly organized
-helix, whereas the
1 portion did not show such a firm structural organization, although it maintained its
-sheet conformation. Our simulations indicate that the hydrophobic core comprising the
2 portion of the aggregate is a crucial stabilizing element in the A
aggregation process. On the basis of these structure-stability findings, the
2 portion emerges as an optimal target for further antiamyloid drug design.
1-42 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
-sheet regions of the aggregates:
1 (residues 18-26) and
2 (residues 31-42). MD simulations reveal that the
-strand twist is a characteristic element of A
-aggregates, permitting a compact, interdigitated packing of side chains from neighboring beta-sheets. The
2 portion formed a tightly organized
-helix, whereas the
1 portion did not show such a firm structural organization, although it maintained its
-sheet conformation. Our simulations indicate that the hydrophobic core comprising the
2 portion of the aggregate is a crucial stabilizing element