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Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations

Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently-developed approach for de novo protein structure determination based on the incorporation of short-distance crosslinking data as constraints in...

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Autores principales: Brodie, Nicholas I., Popov, Konstantin I., Petrotchenko, Evgeniy V., Dokholyan, Nikolay V., Borchers, Christoph H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453469/
https://www.ncbi.nlm.nih.gov/pubmed/30917118
http://dx.doi.org/10.1371/journal.pcbi.1006859
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author Brodie, Nicholas I.
Popov, Konstantin I.
Petrotchenko, Evgeniy V.
Dokholyan, Nikolay V.
Borchers, Christoph H.
author_facet Brodie, Nicholas I.
Popov, Konstantin I.
Petrotchenko, Evgeniy V.
Dokholyan, Nikolay V.
Borchers, Christoph H.
author_sort Brodie, Nicholas I.
collection PubMed
description Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently-developed approach for de novo protein structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD) for the determination of conformational ensemble of the intrinsically disordered protein α-synuclein in the solution. The predicted structures were in agreement with hydrogen-deuterium exchange, circular dichroism, surface modification, and long-distance crosslinking data. We found that α-synuclein is present in solution as an ensemble of rather compact globular conformations with distinct topology and inter-residue contacts, which is well-represented by movements of the large loops and formation of few transient secondary structure elements. Non-amyloid component and C-terminal regions were consistently found to contain β-structure elements and hairpins.
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spelling pubmed-64534692019-04-19 Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations Brodie, Nicholas I. Popov, Konstantin I. Petrotchenko, Evgeniy V. Dokholyan, Nikolay V. Borchers, Christoph H. PLoS Comput Biol Research Article Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently-developed approach for de novo protein structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD) for the determination of conformational ensemble of the intrinsically disordered protein α-synuclein in the solution. The predicted structures were in agreement with hydrogen-deuterium exchange, circular dichroism, surface modification, and long-distance crosslinking data. We found that α-synuclein is present in solution as an ensemble of rather compact globular conformations with distinct topology and inter-residue contacts, which is well-represented by movements of the large loops and formation of few transient secondary structure elements. Non-amyloid component and C-terminal regions were consistently found to contain β-structure elements and hairpins. Public Library of Science 2019-03-27 /pmc/articles/PMC6453469/ /pubmed/30917118 http://dx.doi.org/10.1371/journal.pcbi.1006859 Text en © 2019 Brodie 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Brodie, Nicholas I.
Popov, Konstantin I.
Petrotchenko, Evgeniy V.
Dokholyan, Nikolay V.
Borchers, Christoph H.
Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
title Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
title_full Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
title_fullStr Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
title_full_unstemmed Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
title_short Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
title_sort conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453469/
https://www.ncbi.nlm.nih.gov/pubmed/30917118
http://dx.doi.org/10.1371/journal.pcbi.1006859
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