The amyloid _ -peptides (A _ s), containing 39¨C43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of A _ 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 _ -helix to _ -sheet conformational transition for A _ 40 was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with _ -sheet components were observed as intermediates in the unfolding pathway of A _ 40. Four glycines (G25, G29, G33, and G37) are important for A _ 40 to form _ -sheet in aqueous solution; mutations of these glycines to alanines almost abolished the _ -sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of A _ 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 _ 40 aggregation and amyloid fibril formation. The results ofMDsimulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of A _ and amyloid fibril formation.