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Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation – A Systematic Computational Study
Amyloid-[Image: see text] (A[Image: see text]) oligomers play a crucial role in Alzheimer’s disease due to their neurotoxic aggregation properties. Fibrillar A[Image: see text] oligomerization can lead to protofilaments and protofilament pairs via oligomer elongation and oligomer association, respec...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729696/ https://www.ncbi.nlm.nih.gov/pubmed/23936224 http://dx.doi.org/10.1371/journal.pone.0070521 |
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author | Kahler, Anna Sticht, Heinrich Horn, Anselm H. C. |
author_facet | Kahler, Anna Sticht, Heinrich Horn, Anselm H. C. |
author_sort | Kahler, Anna |
collection | PubMed |
description | Amyloid-[Image: see text] (A[Image: see text]) oligomers play a crucial role in Alzheimer’s disease due to their neurotoxic aggregation properties. Fibrillar A[Image: see text] oligomerization can lead to protofilaments and protofilament pairs via oligomer elongation and oligomer association, respectively. Small fibrillar oligomers adopt the protofilament topology, whereas fibrils contain at least protofilament pairs. To date, the underlying growth mechanism from oligomers to the mature fibril still remains to be elucidated. Here, we performed all-atom molecular dynamics simulations in explicit solvent on single layer-like protofilaments and fibril-like protofilament pairs of different size ranging from the tetramer to the 48-mer. We found that the initial U-shaped topology per monomer is maintained over time in all oligomers. The observed deviations of protofilaments from the starting structure increase significantly with size due to the twisting of the in-register parallel [Image: see text]-sheets. This twist causes long protofilaments to be unstable and leads to a breakage. Protofilament pairs, which are stabilized by a hydrophobic interface, exhibit more fibril-like properties such as the overall structure and the twist angle. Thus, they can act as stable conformational templates for further fibril growth. Key properties like the twist angle, shape complementarity, and energetics show a size-dependent behavior so that small oligomers favor the protofilament topology, whereas large oligomers favor the protofilament pair topology. The region for this conformational transition is at the size of approximately twelve A[Image: see text] monomers. From that, we propose the following growth mechanism from A[Image: see text] oligomers to fibrils: (1) elongation of short protofilaments; (2) breakage of large protofilaments; (3) formation of short protofilament pairs; and (4) elongation of protofilament pairs. |
format | Online Article Text |
id | pubmed-3729696 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37296962013-08-09 Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation – A Systematic Computational Study Kahler, Anna Sticht, Heinrich Horn, Anselm H. C. PLoS One Research Article Amyloid-[Image: see text] (A[Image: see text]) oligomers play a crucial role in Alzheimer’s disease due to their neurotoxic aggregation properties. Fibrillar A[Image: see text] oligomerization can lead to protofilaments and protofilament pairs via oligomer elongation and oligomer association, respectively. Small fibrillar oligomers adopt the protofilament topology, whereas fibrils contain at least protofilament pairs. To date, the underlying growth mechanism from oligomers to the mature fibril still remains to be elucidated. Here, we performed all-atom molecular dynamics simulations in explicit solvent on single layer-like protofilaments and fibril-like protofilament pairs of different size ranging from the tetramer to the 48-mer. We found that the initial U-shaped topology per monomer is maintained over time in all oligomers. The observed deviations of protofilaments from the starting structure increase significantly with size due to the twisting of the in-register parallel [Image: see text]-sheets. This twist causes long protofilaments to be unstable and leads to a breakage. Protofilament pairs, which are stabilized by a hydrophobic interface, exhibit more fibril-like properties such as the overall structure and the twist angle. Thus, they can act as stable conformational templates for further fibril growth. Key properties like the twist angle, shape complementarity, and energetics show a size-dependent behavior so that small oligomers favor the protofilament topology, whereas large oligomers favor the protofilament pair topology. The region for this conformational transition is at the size of approximately twelve A[Image: see text] monomers. From that, we propose the following growth mechanism from A[Image: see text] oligomers to fibrils: (1) elongation of short protofilaments; (2) breakage of large protofilaments; (3) formation of short protofilament pairs; and (4) elongation of protofilament pairs. Public Library of Science 2013-07-31 /pmc/articles/PMC3729696/ /pubmed/23936224 http://dx.doi.org/10.1371/journal.pone.0070521 Text en © 2013 Kahler et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kahler, Anna Sticht, Heinrich Horn, Anselm H. C. Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation – A Systematic Computational Study |
title | Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation – A Systematic Computational Study |
title_full | Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation – A Systematic Computational Study |
title_fullStr | Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation – A Systematic Computational Study |
title_full_unstemmed | Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation – A Systematic Computational Study |
title_short | Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation – A Systematic Computational Study |
title_sort | conformational stability of fibrillar amyloid-beta oligomers via protofilament pair formation – a systematic computational study |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729696/ https://www.ncbi.nlm.nih.gov/pubmed/23936224 http://dx.doi.org/10.1371/journal.pone.0070521 |
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