Solution structures of micelle-bound amyloid β-(1-40) and β-(1-42) peptides of Alzheimer’s disease 1 1Edited by P. E. Wright

Shao, Huili; Jao, Shu-Chuan; Ma, Ke; Zagorski, Michael G.

doi:10.1006/jmbi.1998.2348

Cited by 294 publications

(405 citation statements)

References 117 publications

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“…Detailed analyses were performed for the conformational transition of A␤ 40 based on 12 MD trajectories. The results demonstrate that A␤ 40 adopts different conformations in aqueous solution and in the DPPC bilayer, which are in agreement with the experimental results (14)(15)(16)(17)(18)(19)(20)(21)(22). Six MD simulations (A1-A6) with different initial velocities assigned to the atoms and different temperatures consistently produced the same result that conformational transition of A␤ 40 from ␣-helix to ␤-sheet occurs in aqueous solution ( Figs.…”

Section: Discussionsupporting

confidence: 87%

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Conformational transition of amyloid β-peptide

Shen

Luo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

242

259

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The amyloid ␤-peptides (A␤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␤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 of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of A␤ and amyloid fibril formation. molecular dynamics simulation A lzheimer's disease (AD), a neurodegenerative disorder, is pathologically characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles in the brain (1). The major components of the plaques are amyloid ␤-peptides (A␤s) consisting of 39-43 residues that are proteolytically derived from the widely distributed transmembrane amyloid precursor glycoprotein (APP) (2-4). The amyloid hypothesis suggests that misfolding of A␤ leads to its dysfunctions and fibrillization; the latter is associated with a cascade of neuropathogenetic events to produce the cognitive and behavioral decline hallmarks of AD (4-6). Recently, however, compelling evidence has emerged that not the fibrillar aggregates but the dominant ␤-sheet structure of oligomers and fibril intermediates (protofibrils) are neurotoxic and might be the determinant pathogenic factor in AD (7-9). For example, Walsh et al. (8) demonstrated that cerebral microinjection of cell medium containing abundant A␤ monomers and oligomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation in rats in vivo. The conflict between the amyloid hypothesis and these new emerging experimental observations has stimulated more and more researchers to study the earliest phases of A␤ assembly and to explore the intrinsic properties of A␤s and the conformational dynamic behaviors of the A␤ monomer (9-15).In addition, it has been established experimentally that the major secondary structure adopted by A␤ depends on the environment. The A␤ monomer favors an ␣-helix structure in a me...

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Section: Discussionsupporting

confidence: 87%

“…The A␤ monomer favors an ␣-helix structure in a membrane or membrane-mimicking environment such as ionic detergents (15)(16)(17)(18)(19). In contrast, A␤ exists mainly as a random coil with few components of ␣-helix and͞or ␤-sheet conformations in aqueous solution (14,18,(20)(21)(22).…”

mentioning

confidence: 99%

Conformational transition of amyloid β-peptide

Shen

Luo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

242

259

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“…At room temperature, the replica-exchange simulation samples a much wider part of configuration space as the conventional canonical MD run. 26 At room temperature, the A␤ monomer does not have a unique folded conformation in water but adopts one of the several low energy structures as seen, for instance, in Fig. 3.…”

Section: Resultsmentioning

confidence: 98%

“…On the other hand, NMR results show conformations varying from ␣-helical structure in a nonpolar solution 8 to disordered N-terminal and C-terminal tails with consistent turn regions as determined by electrospray mass spectroscopy and implicit solvent MD. 26,27 The side chain of most hydrophobic residues found in the shorter arm point outward, providing a hydrophobic platform for an association between A␤ monomer. This is consistent with the simulation by Tarus et al 28 of dimerization of A␤ 10-35 using umbrella sampling and MD.…”

Section: -3mentioning

confidence: 99%

“…Ma and Nussinov 11 suggested that at high temperature fragments A␤ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] and A␤ form a strand-loop-strand structure with parallel ␤ sheet, with an interior salt bridge between Asp23 and Lys28 residues as a major element of the fibril structure. On the other hand, computational studies using coarse-grained as well as atomistic atom models suggest the formation of antiparallel ␤ sheets by A␤ [16][17][18][19][20][21][22] subpeptides.…”

Section: Introductionmentioning

confidence: 99%

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The Alzheimer’s β amyloid (Aβ1–39) monomer in an implicit solvent

Anand

Nandel

Hansmann

2008

The Journal of Chemical Physics

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Amyloids and Protein Aggregation—Analytical Methods

Li¹,

Rahimi²,

Sinha³

et al. 2009

Encyclopedia of Analytical Chemistry

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More than 30 diseases are associated with amyloid‐forming proteins, which undergo conformational alterations and “misfolding” under particular conditions. These proteins deposit as insoluble proteinaceous aggregates generating disease‐specific histopathologic lesions. The proteins contributing to each disease have dissimilar sequences and native structures, yet they share the commonality of forming insoluble amyloid aggregates characterized by fibrillar morphology and cross‐β structure. Presently, it is thought that the predominant agents causing cell toxicity and tissue damage are soluble, prefibrillar assemblies of these proteins. Because of the metastable nature of these prefibrillar assemblies and the noncrystalline nature of fibrillar protein aggregates, structural study of amyloid proteins is difficult. As a result, structural characterization of these proteins is typically done using combinations of low‐resolution analytical methods. Here, we present a compendium of analytical methods used to study the secondary, tertiary, and quaternary structures, and morphology of prefibrillar and fibrillar assemblies of amyloid‐forming proteins.

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Solution structures of micelle-bound amyloid β-(1-40) and β-(1-42) peptides of Alzheimer’s disease 1 1Edited by P. E. Wright

Cited by 294 publications

References 117 publications

Conformational transition of amyloid β-peptide

Conformational transition of amyloid β-peptide

The Alzheimer’s β amyloid (Aβ1–39) monomer in an implicit solvent

Amyloids and Protein Aggregation—Analytical Methods

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