The Alzheimer's Peptide Aβ Adopts a Collapsed Coil Structure in Water

Zhang, S.; Iwata, Kunihiro; Lachenmann, M.J.; Peng, Jeffrey W.; Li, S.; Stimson, Evelyn R.; Lu, Yi An; Félix, Arthur; Maggio, John E.; Lee, J.P.

doi:10.1006/jsbi.2000.4288

Cited by 333 publications

(490 citation statements)

References 29 publications

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“…These five simulations revealed that, in aqueous solution and room temperature (300 K), A␤ 40 is statistically composed by Ϸ26% helix, Ϸ12% ␤-sheet, and Ϸ62% coil components (Table 2). This finding is in good agreement with the NMR observations (14,18,22), which indicated that, in aqueous solution, the monomer of A␤ 40 favors random coil structure, but ␣-helix and ␤-sheet conformations still exist. Interestingly, the MD simulations indicate that helix͞␤-strand mixed conformations exist in the trajectory of the A␤ 40 conformational transition.…”

Section: Resultssupporting

confidence: 91%

“…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: 88%

“…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)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

“…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). However, x-ray diffraction measurements on oriented fibril bundles have indicated an extended ␤-sheet structure for Alzheimer's ␤-amyloid fibrils, with peptide chains in ␤-strand conformations running approximately perpendicular to the fibril axis and hydrogen bonds between peptide chains in each layer occurring roughly parallel to the fiber axis (23,24).…”

mentioning

confidence: 99%

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Conformational transition of amyloid β-peptide

Shen

Luo

et al. 2005

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

247

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: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Conformational transition of amyloid β-peptide

Shen

Luo

et al. 2005

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

247

259

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“…Docking studies of AChE with its agonists (ACh and Aβ) Docking studies were carried out between the selected hAChE-ligand complex with Aβ (PDB ID: 1HZ3) [49] and ACh to evaluate their ability to inhibit the interactions between AChE and their agonists, respectively. Previously, to gain the information of native hAChE (ligand free protein PDB ID: 1B41) interaction with their agonists, a separate docking study between native hAChE and their agonists was also performed.…”

Section: Molecular Dockingmentioning

confidence: 99%

Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase

et al. 2012

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Anomalous action of human acetylcholinesterase (hAChE) in Alzheimer's disease (AD) was restrained by various AChE inhibitors, of which the specific and potent lead candidate Donepezil is used for treating the disease AD. Besides the specificity, the observed undesirable side effects caused by Donepezil invoked the quest for new lead molecules with the increased potency and specificity for AChE. The present study elucidates the potency of six 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives to form a specific interaction with the peripheral anionic site and catalytic anionic subsite residues of hAChE. The NMSMs were prepared in good yield from 1,1-di(methylsulfanyl)-2-nitroethylene and primary amine (or) amino acid esters. In silico interaction analysis reveals specific and potent interactions between hAChE and selected ligand molecules. The sitespecific interactions formed between these molecules also results in a conformational change in the orientation of active site residues of hAChE, which prevents them from being accessed by beta-amyloid protein (Aβ), which is a causative agent for amyloid plaque formation and acetylcholine (ACh). In silico interaction analysis between the ligand-bounded hAChE with Aß and ACh confirms this observation. The variation in the conformation of hAChE associated with the decreased ability of Aβ and ACh to access the respective functional residues of hAChE induced by the novel NMSMs favors their selection for in vivo analysis to present themselves as new members of hAChE inhibitors.

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Amyloid Precursor Protein

Leong

Barnham

Multhaup

et al. 2004

Handbook of Metalloproteins

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The amyloid‐precursor protein (APP) is a transmembrane glycoprotein implicated in the pathogenesis of Alzheimer's disease (AD). In mammals, there are two paralogues of APP termed amyloid precursor‐like protein 1 (APLP1) and amyloid precursor‐like protein 2 (APLP2). Orthologues of APP also exist, suggesting a conserved function vital throughout evolution. APP is a multidomain protein with metal‐binding sites critical to its function. There are two copper‐binding domains, one lies in the N‐terminus, adjacent to the zinc‐binding domain, and the other is in the amyloid‐beta (Aβ) domain. Aβ is derived via a series of protease cleavages of APP by the secretases, and is the main constituent of the amyloid plaques that are a key pathological hallmark of AD. The physiological role of APP is as yet unknown. It can reduce Cu 2+ to Cu + , and the physiological and three‐dimensional structure suggests a role as a copper chaperone. The binding of Cu to Aβ is toxic to neuronal cultures, and this may contribute to the oxidative stress that is commonly observed in AD.

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The Alzheimer's Peptide Aβ Adopts a Collapsed Coil Structure in Water

Cited by 333 publications

References 29 publications

Conformational transition of amyloid β-peptide

Conformational transition of amyloid β-peptide

Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase

Amyloid Precursor Protein

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