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Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution
Protein aggregation into amyloid fibrils is the archetype of aberrant biomolecular self-assembly processes, with more than 50 associated diseases that are mostly uncurable. Understanding aggregation mechanisms is thus of fundamental importance and goes in parallel with the structural characterizatio...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245614/ https://www.ncbi.nlm.nih.gov/pubmed/35737839 http://dx.doi.org/10.1073/pnas.2203181119 |
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author | Scalone, Emanuele Broggini, Luca Visentin, Cristina Erba, Davide Bačić Toplek, Fran Peqini, Kaliroi Pellegrino, Sara Ricagno, Stefano Paissoni, Cristina Camilloni, Carlo |
author_facet | Scalone, Emanuele Broggini, Luca Visentin, Cristina Erba, Davide Bačić Toplek, Fran Peqini, Kaliroi Pellegrino, Sara Ricagno, Stefano Paissoni, Cristina Camilloni, Carlo |
author_sort | Scalone, Emanuele |
collection | PubMed |
description | Protein aggregation into amyloid fibrils is the archetype of aberrant biomolecular self-assembly processes, with more than 50 associated diseases that are mostly uncurable. Understanding aggregation mechanisms is thus of fundamental importance and goes in parallel with the structural characterization of the transient oligomers formed during the process. Oligomers have been proven elusive to high-resolution structural techniques, while the large sizes and long time scales, typical of aggregation processes, have limited the use of computational methods to date. To surmount these limitations, we here present multi-eGO, an atomistic, hybrid structure-based model which, leveraging the knowledge of monomers conformational dynamics and of fibril structures, efficiently captures the essential structural and kinetics aspects of protein aggregation. Multi-eGO molecular dynamics simulations can describe the aggregation kinetics of thousands of monomers. The concentration dependence of the simulated kinetics, as well as the structural features of the resulting fibrils, are in qualitative agreement with in vitro experiments carried out on an amyloidogenic peptide from Transthyretin, a protein responsible for one of the most common cardiac amyloidoses. Multi-eGO simulations allow the formation of primary nuclei in a sea of transient lower-order oligomers to be observed over time and at atomic resolution, following their growth and the subsequent secondary nucleation events, until the maturation of multiple fibrils is achieved. Multi-eGO, combined with the many experimental techniques deployed to study protein aggregation, can provide the structural basis needed to advance the design of molecules targeting amyloidogenic diseases. |
format | Online Article Text |
id | pubmed-9245614 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-92456142022-12-23 Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution Scalone, Emanuele Broggini, Luca Visentin, Cristina Erba, Davide Bačić Toplek, Fran Peqini, Kaliroi Pellegrino, Sara Ricagno, Stefano Paissoni, Cristina Camilloni, Carlo Proc Natl Acad Sci U S A Biological Sciences Protein aggregation into amyloid fibrils is the archetype of aberrant biomolecular self-assembly processes, with more than 50 associated diseases that are mostly uncurable. Understanding aggregation mechanisms is thus of fundamental importance and goes in parallel with the structural characterization of the transient oligomers formed during the process. Oligomers have been proven elusive to high-resolution structural techniques, while the large sizes and long time scales, typical of aggregation processes, have limited the use of computational methods to date. To surmount these limitations, we here present multi-eGO, an atomistic, hybrid structure-based model which, leveraging the knowledge of monomers conformational dynamics and of fibril structures, efficiently captures the essential structural and kinetics aspects of protein aggregation. Multi-eGO molecular dynamics simulations can describe the aggregation kinetics of thousands of monomers. The concentration dependence of the simulated kinetics, as well as the structural features of the resulting fibrils, are in qualitative agreement with in vitro experiments carried out on an amyloidogenic peptide from Transthyretin, a protein responsible for one of the most common cardiac amyloidoses. Multi-eGO simulations allow the formation of primary nuclei in a sea of transient lower-order oligomers to be observed over time and at atomic resolution, following their growth and the subsequent secondary nucleation events, until the maturation of multiple fibrils is achieved. Multi-eGO, combined with the many experimental techniques deployed to study protein aggregation, can provide the structural basis needed to advance the design of molecules targeting amyloidogenic diseases. National Academy of Sciences 2022-06-23 2022-06-28 /pmc/articles/PMC9245614/ /pubmed/35737839 http://dx.doi.org/10.1073/pnas.2203181119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Scalone, Emanuele Broggini, Luca Visentin, Cristina Erba, Davide Bačić Toplek, Fran Peqini, Kaliroi Pellegrino, Sara Ricagno, Stefano Paissoni, Cristina Camilloni, Carlo Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution |
title | Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution |
title_full | Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution |
title_fullStr | Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution |
title_full_unstemmed | Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution |
title_short | Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution |
title_sort | multi-ego: an in silico lens to look into protein aggregation kinetics at atomic resolution |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245614/ https://www.ncbi.nlm.nih.gov/pubmed/35737839 http://dx.doi.org/10.1073/pnas.2203181119 |
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