Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.

The pre-fibrillar stages of amyloid formation have been implicated in cellular toxicity, but have proved to be challenging to study directly in experiments and simulations. Rational strategies to suppress the formation of toxic amyloid oligomers require a better understanding of the mechanisms by wh...

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Autores principales:	Noah S Bieler, Tuomas P J Knowles, Daan Frenkel, Robert Vácha
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b0b92e549d49468ca71606453f614e20
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spelling	oai:doaj.org-article:b0b92e549d49468ca71606453f614e202021-11-18T05:52:48ZConnecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.1553-734X1553-735810.1371/journal.pcbi.1002692https://doaj.org/article/b0b92e549d49468ca71606453f614e202012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23071427/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The pre-fibrillar stages of amyloid formation have been implicated in cellular toxicity, but have proved to be challenging to study directly in experiments and simulations. Rational strategies to suppress the formation of toxic amyloid oligomers require a better understanding of the mechanisms by which they are generated. We report Dynamical Monte Carlo simulations that allow us to study the early stages of amyloid formation. We use a generic, coarse-grained model of an amyloidogenic peptide that has two internal states: the first one representing the soluble random coil structure and the second one the [Formula: see text]-sheet conformation. We find that this system exhibits a propensity towards fibrillar self-assembly following the formation of a critical nucleus. Our calculations establish connections between the early nucleation events and the kinetic information available in the later stages of the aggregation process that are commonly probed in experiments. We analyze the kinetic behaviour in our simulations within the framework of the theory of classical nucleated polymerisation, and are able to connect the structural events at the early stages in amyloid growth with the resulting macroscopic observables such as the effective nucleus size. Furthermore, the free-energy landscapes that emerge from these simulations allow us to identify pertinent properties of the monomeric state that could be targeted to suppress oligomer formation.Noah S BielerTuomas P J KnowlesDaan FrenkelRobert VáchaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 10, p e1002692 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Noah S Bieler Tuomas P J Knowles Daan Frenkel Robert Vácha Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.
description	The pre-fibrillar stages of amyloid formation have been implicated in cellular toxicity, but have proved to be challenging to study directly in experiments and simulations. Rational strategies to suppress the formation of toxic amyloid oligomers require a better understanding of the mechanisms by which they are generated. We report Dynamical Monte Carlo simulations that allow us to study the early stages of amyloid formation. We use a generic, coarse-grained model of an amyloidogenic peptide that has two internal states: the first one representing the soluble random coil structure and the second one the [Formula: see text]-sheet conformation. We find that this system exhibits a propensity towards fibrillar self-assembly following the formation of a critical nucleus. Our calculations establish connections between the early nucleation events and the kinetic information available in the later stages of the aggregation process that are commonly probed in experiments. We analyze the kinetic behaviour in our simulations within the framework of the theory of classical nucleated polymerisation, and are able to connect the structural events at the early stages in amyloid growth with the resulting macroscopic observables such as the effective nucleus size. Furthermore, the free-energy landscapes that emerge from these simulations allow us to identify pertinent properties of the monomeric state that could be targeted to suppress oligomer formation.
format	article
author	Noah S Bieler Tuomas P J Knowles Daan Frenkel Robert Vácha
author_facet	Noah S Bieler Tuomas P J Knowles Daan Frenkel Robert Vácha
author_sort	Noah S Bieler
title	Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.
title_short	Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.
title_full	Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.
title_fullStr	Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.
title_full_unstemmed	Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.
title_sort	connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/b0b92e549d49468ca71606453f614e20
work_keys_str_mv	AT noahsbieler connectingmacroscopicobservablesandmicroscopicassemblyeventsinamyloidformationusingcoarsegrainedsimulations AT tuomaspjknowles connectingmacroscopicobservablesandmicroscopicassemblyeventsinamyloidformationusingcoarsegrainedsimulations AT daanfrenkel connectingmacroscopicobservablesandmicroscopicassemblyeventsinamyloidformationusingcoarsegrainedsimulations AT robertvacha connectingmacroscopicobservablesandmicroscopicassemblyeventsinamyloidformationusingcoarsegrainedsimulations
_version_	1718424748894978048

Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations.

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