Dataset Information

Conformational transition of amyloid beta-peptide.

ABSTRACT: 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.

SUBMITTER: Xu Y

PROVIDER: S-EPMC556260 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature

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Conformational transition of amyloid beta-peptide.

Xu Yechun Y Shen Jianhua J Luo Xiaomin X Zhu Weiliang W Chen Kaixian K Ma Jianpeng J Jiang Hualiang H

Proceedings of the National Academy of Sciences of the United States of America 20050330 15

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 obser ...[more]

PMID: 15800039

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Project description:The amyloid beta (Aβ) peptide represents a 37 to 49 amino acids endoproteolytic fragment of the amyloid precursor protein. The cellular biology that governs the formation and clearance of Aβ has been understood to play a critical role in Alzheimer’s disease (AD). The primary objective of this study was to generate an in-depth inventory of human brain proteins that oligomeric preparations of Aβ1-42 can bind to using an unbiased in vitro discovery approach. Synthetic Aβ1-42 peptides and a brain extract generated from adult human frontal lobe tissue served in these studies as baits and biological source material, respectively. oAβ1-42 was prepared by aggregating the peptide at 4 ºC for 24 h, using previously described procedures known to generate amyloid-β-derived diffusible ligands (ADDLs). Because the interaction with a given binding partner may rely on a binding epitope that comprises N- or C-terminal residues of Aβ1-42, two separate experiments (I and II) were conducted, which differed in the orientation the oAβ1-42 bait was tethered to the affinity matrix. To facilitate meaningful comparisons across experiments, the method of Aβ1-42 capture was not based on immunoaffinity reagents. Instead, alternative Aβ1-42 baits were equipped with biotin moieties attached to the N- or C-terminus by a 6-carbon linker chain, enabling their consistent affinity-capture on streptavidin agarose matrices. Biotin-saturated streptavidin agarose matrices served as negative controls and three biological replicates of samples and controls were generated for each of the three separate interactome datasets by reproducing the affinity-capture step side-by-side on three separate streptavidin agarose affinity matrices that had been saturated with the biotinylated baits. To identify differences in protein-protein interactions of monomeric versus oligomeric Aβ1-42, a 3rd interactome experiment was conducted in which oAβ1-42-biotin or mAβ1-42-biotin served as baits. Digitonin-solubilized brain extracts, which are known to comprise extracellular and most cellular proteins (except for nuclear proteins) served as biological starting material, consistent with the main subcellular areas previously reported to harbor Aβ. Following extensive washes of affinity matrices in their protein-bound state, binders to the bait peptides were eluted by rapid acidification, fully denatured in 9 M urea, and trypsinized. To avoid notorious confounders related to variances in the subsequent handling and analysis of samples, individual peptide mixtures were labeled with distinct isobaric tandem mass tags (TMT) in a six-plex format, then combined and concomitantly subjected to ZipTip-based pre-analysis clean-up by strong cation exchange (SCX) and reversed phase (RP) separation. Four-hour split-free reversed phase nanospray separations were online coupled to an Orbitrap Fusion Tribrid mass spectrometer, which was configured to run an MS3 analysis method.

Dataset Information

Conformational transition of amyloid beta-peptide.

Publications

Conformational transition of amyloid beta-peptide.

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