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

Nicholas I. Brodie, Konstantin I. Popov, Evgeniy V. Petrotchenko, Nikolay V. Dokholyan, Christoph H. Borchers

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1006859
JournalPLoS computational biology
Volume15
Issue number3
DOIs
StatePublished - Mar 2019

Fingerprint

Synucleins
Discrete Dynamics
molecular dynamics
protein structure
Molecular Dynamics Simulation
crosslinking
Crosslinking
Molecular dynamics
Ensemble
Intrinsically Disordered Proteins
circular dichroism spectroscopy
Proteins
Surface Modification
Protein Structure Prediction
protein
deuterium
Deuterium
Proteomics
Computer simulation
Protein Structure

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Cite this

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title = "Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations",
abstract = "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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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.

In: PLoS computational biology, Vol. 15, No. 3, e1006859, 03.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations

AU - Brodie, Nicholas I.

AU - Popov, Konstantin I.

AU - Petrotchenko, Evgeniy V.

AU - Dokholyan, Nikolay V.

AU - Borchers, Christoph H.

PY - 2019/3

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AB - 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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