Cargando…

Mechanisms for the inhibition of amyloid aggregation by small ligands

The formation of amyloid aggregates is the hallmark of systemic and neurodegenerative disorders, also known as amyloidoses. Many proteins have been found to aggregate into amyloid-like fibrils and this process is recognized as a general tendency of polypeptides. Lysozyme, an antibacterial protein, i...

Descripción completa

Detalles Bibliográficos
Autores principales: Ramazzotti, Matteo, Melani, Fabrizio, Marchi, Laura, Mulinacci, Nadia, Gestri, Stefano, Tiribilli, Bruno, Degl'Innocenti, Donatella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041158/
https://www.ncbi.nlm.nih.gov/pubmed/27512096
http://dx.doi.org/10.1042/BSR20160101
_version_ 1782456357388025856
author Ramazzotti, Matteo
Melani, Fabrizio
Marchi, Laura
Mulinacci, Nadia
Gestri, Stefano
Tiribilli, Bruno
Degl'Innocenti, Donatella
author_facet Ramazzotti, Matteo
Melani, Fabrizio
Marchi, Laura
Mulinacci, Nadia
Gestri, Stefano
Tiribilli, Bruno
Degl'Innocenti, Donatella
author_sort Ramazzotti, Matteo
collection PubMed
description The formation of amyloid aggregates is the hallmark of systemic and neurodegenerative disorders, also known as amyloidoses. Many proteins have been found to aggregate into amyloid-like fibrils and this process is recognized as a general tendency of polypeptides. Lysozyme, an antibacterial protein, is a well-studied model since it is associated in human with systemic amyloidosis and that is widely available from chicken eggs (HEWL, hen egg white lysozyme). In the present study we investigated the mechanism of interaction of aggregating HEWL with rosmarinic acid and resveratrol, that we verified to be effective and ineffective, respectively, in inhibiting aggregate formation. We used a multidisciplinary strategy to characterize such effects, combining biochemical and biophysical methods with molecular dynamics (MD) simulations on the HEWL peptide 49–64 to gain insights into the mechanisms and energy variations associated to amyloid formation and inhibition. MD revealed that neither resveratrol nor rosmarinic acid were able to compete with the initial formation of the β-sheet structure. We then tested the association of two β-sheets, representing the model of an amyloid core structure. MD showed that rosmarinic acid displayed an interaction energy and a contact map comparable to that of sheet pairings. On the contrary, resveratrol association energy was found to be much lower and its contact map largely different than that of sheet pairings. The overall characterization elucidated a possible mechanism explaining why, in this model, resveratrol is inactive in blocking fibril formation, whereas rosmarinic acid is instead a powerful inhibitor.
format Online
Article
Text
id pubmed-5041158
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Portland Press Ltd.
record_format MEDLINE/PubMed
spelling pubmed-50411582016-10-13 Mechanisms for the inhibition of amyloid aggregation by small ligands Ramazzotti, Matteo Melani, Fabrizio Marchi, Laura Mulinacci, Nadia Gestri, Stefano Tiribilli, Bruno Degl'Innocenti, Donatella Biosci Rep Original Papers The formation of amyloid aggregates is the hallmark of systemic and neurodegenerative disorders, also known as amyloidoses. Many proteins have been found to aggregate into amyloid-like fibrils and this process is recognized as a general tendency of polypeptides. Lysozyme, an antibacterial protein, is a well-studied model since it is associated in human with systemic amyloidosis and that is widely available from chicken eggs (HEWL, hen egg white lysozyme). In the present study we investigated the mechanism of interaction of aggregating HEWL with rosmarinic acid and resveratrol, that we verified to be effective and ineffective, respectively, in inhibiting aggregate formation. We used a multidisciplinary strategy to characterize such effects, combining biochemical and biophysical methods with molecular dynamics (MD) simulations on the HEWL peptide 49–64 to gain insights into the mechanisms and energy variations associated to amyloid formation and inhibition. MD revealed that neither resveratrol nor rosmarinic acid were able to compete with the initial formation of the β-sheet structure. We then tested the association of two β-sheets, representing the model of an amyloid core structure. MD showed that rosmarinic acid displayed an interaction energy and a contact map comparable to that of sheet pairings. On the contrary, resveratrol association energy was found to be much lower and its contact map largely different than that of sheet pairings. The overall characterization elucidated a possible mechanism explaining why, in this model, resveratrol is inactive in blocking fibril formation, whereas rosmarinic acid is instead a powerful inhibitor. Portland Press Ltd. 2016-09-29 /pmc/articles/PMC5041158/ /pubmed/27512096 http://dx.doi.org/10.1042/BSR20160101 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution Licence 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Papers
Ramazzotti, Matteo
Melani, Fabrizio
Marchi, Laura
Mulinacci, Nadia
Gestri, Stefano
Tiribilli, Bruno
Degl'Innocenti, Donatella
Mechanisms for the inhibition of amyloid aggregation by small ligands
title Mechanisms for the inhibition of amyloid aggregation by small ligands
title_full Mechanisms for the inhibition of amyloid aggregation by small ligands
title_fullStr Mechanisms for the inhibition of amyloid aggregation by small ligands
title_full_unstemmed Mechanisms for the inhibition of amyloid aggregation by small ligands
title_short Mechanisms for the inhibition of amyloid aggregation by small ligands
title_sort mechanisms for the inhibition of amyloid aggregation by small ligands
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041158/
https://www.ncbi.nlm.nih.gov/pubmed/27512096
http://dx.doi.org/10.1042/BSR20160101
work_keys_str_mv AT ramazzottimatteo mechanismsfortheinhibitionofamyloidaggregationbysmallligands
AT melanifabrizio mechanismsfortheinhibitionofamyloidaggregationbysmallligands
AT marchilaura mechanismsfortheinhibitionofamyloidaggregationbysmallligands
AT mulinaccinadia mechanismsfortheinhibitionofamyloidaggregationbysmallligands
AT gestristefano mechanismsfortheinhibitionofamyloidaggregationbysmallligands
AT tiribillibruno mechanismsfortheinhibitionofamyloidaggregationbysmallligands
AT deglinnocentidonatella mechanismsfortheinhibitionofamyloidaggregationbysmallligands