Journal article
Fully Atomistic A beta 40 and A beta 42 Oligomers in Water: Observation of Porelike Conformations
Journal of chemical theory and computation, v 13(9), pp 4567-4583
01 Sep 2017
PMID: 28727426
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Oligomers formed by amyloid beta-protein (A beta) are central to Alzheimer's disease (AD) pathology, yet their structure remains elusive. Of the two predominant A beta alloforms, A beta 40 and A beta 42, the latter is more strongly associated with AD. Here, we structurally characterized A beta 40 and A beta 42 monomers through pentamers which were converted from previously derived coarse-grained (DMD4B-HYDRA) simulations into all-atom conformations and subjected to explicit-solvent MD. Free energy landscapes revealed that structural differences between A beta 40 and A beta 42 conformations increase With oligomer order up to trimers. All conformations display high statistical coil and turn content (40-50%) with minor beta-strand and a-he lical content (<10%). A beta 40 tetramers and pentamers exhibit significantly more elongated morphologies than the respective A,542 conformations. Unlike the initial DMD4B-HYDRA conformations, fully atomistic A beta 40 and A beta 42 trimers, tetramers, and pentamers form water-permeable pores, whereby the tendency for pore formation sharply increased with oligomer order and is the highest for A,642 pentamers. Previous studies reported that A beta oligomers form ion channels when embedded into a cellular membrane, which causes an abnormal ion flux and eventually leads to cell death. Our findings reveal an extraordinary ability of A beta oligomers to form pores in pure water prior to their insertion into a membrane and thus provide support to the ion channel hypothesis of AD.
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Details
- Title
- Fully Atomistic A beta 40 and A beta 42 Oligomers in Water: Observation of Porelike Conformations
- Creators
- Matthew J. Voelker - Drexel UniversityBogdan Barz - Heinrich Heine University DüsseldorfBrigita Urbanc - Drexel University
- Publication Details
- Journal of chemical theory and computation, v 13(9), pp 4567-4583
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 17
- Grant note
- National Science Foundation; National Science Foundation (NSF) PHYS100030 / Purdue University
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000410867500053
- Scopus ID
- 2-s2.0-85029221035
- Other Identifier
- 991019168576104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Physical
- Physics, Atomic, Molecular & Chemical