Conformational transition of amyloid beta-peptide.
The amyloid beta-peptides (Abetas), containing 39-43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of Abeta(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 alpha-helix to beta-sheet conformational transition for Abeta(40) was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with beta-sheet components were observed as intermediates in the unfolding pathway of Abeta(40). Four glycines (G(25), G(29), G(33), and G(37)) are important for Abeta(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 Abeta(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 Abeta(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 Abeta and amyloid fibril formation.
Xu
Yechun
Y
Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School of Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Shen
Jianhua
J
Luo
Xiaomin
X
Zhu
Weiliang
W
Chen
Kaixian
K
Ma
Jianpeng
J
Jiang
Hualiang
H
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D012996:Solutions / Q000737:chemistry
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D010446:Peptide Fragments; D012996:Solutions; C078592:amyloid beta-protein (1-40); D015060:1,2-Dipalmitoylphosphatidylcholine; D005998:Glycine