Conformational transition of amyloid β-peptide

The amyloid beta-peptides (A beta s), containing 39-43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of A beta(40), 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an a-helix to P-sheet conformational transition for A beta(40) was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with P-sheet components were observed as intermediates in the unfolding pathway of A beta(40). Four glycines (G(25), G(29), G(33), and G(37)) are important for A beta(40) to form beta-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the beta-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of A beta(40) is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for A beta(40) aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of A beta and amyloid fibril formation.