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Thermodynamics of Amyloid-β Fibril Elongation: Atomistic Details of the Transition State
[Image: see text] Amyloid-β (Aβ) fibrils and plaques are one of the hallmarks of Alzheimer’s disease. While the kinetics of fibrillar growth of Aβ have been extensively studied, several vital questions remain. In particular, the atomistic origins of the Arrhenius barrier observed in experiments have...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical
Society
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911799/ https://www.ncbi.nlm.nih.gov/pubmed/29239603 http://dx.doi.org/10.1021/acschemneuro.7b00409 |
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author | Rodriguez, Roberto A. Chen, Liao Y. Plascencia-Villa, Germán Perry, George |
author_facet | Rodriguez, Roberto A. Chen, Liao Y. Plascencia-Villa, Germán Perry, George |
author_sort | Rodriguez, Roberto A. |
collection | PubMed |
description | [Image: see text] Amyloid-β (Aβ) fibrils and plaques are one of the hallmarks of Alzheimer’s disease. While the kinetics of fibrillar growth of Aβ have been extensively studied, several vital questions remain. In particular, the atomistic origins of the Arrhenius barrier observed in experiments have not been elucidated. Employing the familiar thermodynamic integration method, we have directly simulated the dissociation of an Aβ((15–40)) (D23N mutant) peptide from the surface of a filament along its most probable path (MPP) using all-atom molecular dynamics. This allows for a direct calculation of the free energy profile along the MPP, revealing a multipeak energetic barrier between the free peptide state and the aggregated state. By definition of the MPP, this simulated unbinding process represents the reverse of the physical elongation pathway, allowing us to draw biophysically relevant conclusions from the simulation data. Analyzing the detailed atomistic interactions along the MPP, we identify the atomistic origins of these peaks as resulting from the dock-lock mechanism of filament elongation. Careful analysis of the dynamics of filament elongation could prove key to the development of novel therapeutic strategies for amyloid-related diseases. |
format | Online Article Text |
id | pubmed-5911799 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American
Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-59117992018-04-24 Thermodynamics of Amyloid-β Fibril Elongation: Atomistic Details of the Transition State Rodriguez, Roberto A. Chen, Liao Y. Plascencia-Villa, Germán Perry, George ACS Chem Neurosci [Image: see text] Amyloid-β (Aβ) fibrils and plaques are one of the hallmarks of Alzheimer’s disease. While the kinetics of fibrillar growth of Aβ have been extensively studied, several vital questions remain. In particular, the atomistic origins of the Arrhenius barrier observed in experiments have not been elucidated. Employing the familiar thermodynamic integration method, we have directly simulated the dissociation of an Aβ((15–40)) (D23N mutant) peptide from the surface of a filament along its most probable path (MPP) using all-atom molecular dynamics. This allows for a direct calculation of the free energy profile along the MPP, revealing a multipeak energetic barrier between the free peptide state and the aggregated state. By definition of the MPP, this simulated unbinding process represents the reverse of the physical elongation pathway, allowing us to draw biophysically relevant conclusions from the simulation data. Analyzing the detailed atomistic interactions along the MPP, we identify the atomistic origins of these peaks as resulting from the dock-lock mechanism of filament elongation. Careful analysis of the dynamics of filament elongation could prove key to the development of novel therapeutic strategies for amyloid-related diseases. American Chemical Society 2017-12-14 /pmc/articles/PMC5911799/ /pubmed/29239603 http://dx.doi.org/10.1021/acschemneuro.7b00409 Text en Copyright © 2017 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Rodriguez, Roberto A. Chen, Liao Y. Plascencia-Villa, Germán Perry, George Thermodynamics of Amyloid-β Fibril Elongation: Atomistic Details of the Transition State |
title | Thermodynamics of Amyloid-β Fibril Elongation:
Atomistic Details of the Transition State |
title_full | Thermodynamics of Amyloid-β Fibril Elongation:
Atomistic Details of the Transition State |
title_fullStr | Thermodynamics of Amyloid-β Fibril Elongation:
Atomistic Details of the Transition State |
title_full_unstemmed | Thermodynamics of Amyloid-β Fibril Elongation:
Atomistic Details of the Transition State |
title_short | Thermodynamics of Amyloid-β Fibril Elongation:
Atomistic Details of the Transition State |
title_sort | thermodynamics of amyloid-β fibril elongation:
atomistic details of the transition state |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911799/ https://www.ncbi.nlm.nih.gov/pubmed/29239603 http://dx.doi.org/10.1021/acschemneuro.7b00409 |
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