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Effect of Familial ...
Effect of Familial Mutations on the Interconversion of alpha-Helix to beta-Sheet Structures in an Amyloid-Forming Peptide : Insight from Umbrella Sampling Simulations
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- Mudedla, Sathish Kumar (författare)
- KTH,Teoretisk kemi och biologi
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- Murugan, Natarajan Arul (författare)
- KTH,Teoretisk kemi och biologi
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- Ågren, Hans (författare)
- KTH,Teoretisk kemi och biologi,Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China.
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(creator_code:org_t)
- 2018-12-26
- 2019
- Engelska.
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 10:3, s. 1347-1354
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Understanding the initial events of aggregation of amyloid beta monomers to form beta-sheet rich fibrils is useful for the development of therapeutics for Alzheimer's disease. In this context, the changes in energetics involved in the aggregation of helical amyloid beta monomers into beta-sheet rich dimers have been investigated using umbrella sampling simulations and density functional theory calculations. The results from umbrella sampling simulations for the free energy profile for the interconversion closely agree with the results of density functional theory calculations. The results reveal that helical peptides converted to beta-sheet structures through coil-like conformations as intermediates that are mostly stabilized by intramolecular hydrogen bonds. The stabilization of intermediate structures could be a possible way to inhibit fibril formation. Mutations substantially decrease the height of the energy barrier for interconversion from alpha-helix to beta-sheet structure when compared to that of the wild type, something that is attributed to an increase in the number of intramolecular hydrogen bonds between backbone atoms in the coil structures that correspond to a maximum value on the free energy surface. The reduction of the energy barrier leads to an enhancement of the rate of aggregation of amyloid beta monomers upon introduction of various familial mutations, which is consistent with previous experimental reports.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Amyloid forming peptide
- mutation effect on rate of aggregation
- Alzheimer's disease
- free energy for alpha-helix to beta-sheet interconversion
- umbrella sampling simulations
- familial mutations
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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