Conformational Transition of Amyloid β-Peptide

The amyloid β-peptides (Aβs), containing 39-43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of Aβ40, 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 α-helix to β-sheet conformational transition for Aβ40was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with β-sheet components were observed as intermediates in the unfolding pathway of Aβ40. Four glycines ( G25, G29, G33, and G37) are important for Aβ40to form β-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the β-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of Aβ40is 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 Aβ40aggregation 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 Aβ and amyloid fibril formation.