Abstract:
:A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein (1-40) in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers. We explore the structure and stability of both prefibrillar oligomers that consist of mainly antiparallel β-sheets and fibrillar oligomers with only parallel β-sheets. Prefibrillar oligomers are polymorphic but typically take on a cylindrin-like shape composed of mostly antiparallel β-strands. At the concentration of the simulation, the aggregation free energy landscape is nearly downhill. We use umbrella sampling along a structural progress coordinate for interconversion between prefibrillar and fibrillar forms to identify a conversion pathway between these forms. The fibrillar oligomer only becomes favored over its prefibrillar counterpart in the pentamer where an interconversion bottleneck appears. The structural characterization of the pathway along with statistical mechanical perturbation theory allow us to evaluate the effects of concentration on the free energy landscape of aggregation as well as the effects of the Dutch and Arctic mutations associated with early onset of Alzheimer's disease.
journal_name
Proc Natl Acad Sci U S Aauthors
Zheng W,Tsai MY,Chen M,Wolynes PGdoi
10.1073/pnas.1612362113subject
Has Abstractpub_date
2016-10-18 00:00:00pages
11835-11840issue
42eissn
0027-8424issn
1091-6490pii
1612362113journal_volume
113pub_type
杂志文章abstract::By affinity chromatography on heparin-Sepharose, two classes of lipoproteins were separated from high density lipoproteins (HDL) isolated from patients with primary or secondary lecithin:cholesterol acyltransferase (LCATase; EC 2.3.1.43) deficiency and from normal subjects. The unretained fraction, HDL(A), was charact...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1980-05-01 00:00:00
abstract::Bones from a stratified sedimentary deposit in the Puu Naio Cave site on Maui, Hawaiian Islands, reveal the late Holocene extinction of 19 species of birds. The age of the sediment and associated fauna was determined by direct radiocarbon dating (tandem particle accelerator-mass spectrometer; TAMS) of amino acids extr...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.0409373102
更新日期:2005-02-22 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1973-12-01 00:00:00
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更新日期:1991-06-15 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2008-04-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2017-03-28 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1979-03-01 00:00:00
abstract::Taking advantage of a fluorescent Ca(2+) indicator selectively targeted to the trans-Golgi lumen, we here demonstrate that its Ca(2+) homeostatic mechanisms are distinct from those of the other Golgi subcompartments: (i) Ca(2+) uptake depends exclusively on the activity of the secretory pathway Ca(2+) ATPase1 (SPCA1),...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2010-05-18 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2011-02-15 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 临床试验,杂志文章,多中心研究
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更新日期:2018-09-04 00:00:00