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

PLoS Comput Biol. 2019 Mar 27;15(3):e1006859. doi: 10.1371/journal.pcbi.1006859. eCollection 2019 Mar.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Molecular Dynamics Simulation*
  • Protein Conformation
  • Proteomics
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / ultrastructure
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / ultrastructure*


  • Recombinant Proteins
  • alpha-Synuclein

Grants and funding

CHB and the University of Victoria-Genome British Columbia Proteomics Centre are grateful to Genome Canada and Genome British Columbia for financial support through the Genomics Innovation Network (project codes 204PRO for operations and 214PRO for technology development) [], and the Genomics Technology Platform (264PRO) [;]. CHB is also grateful for support from the Natural Sciences and Engineering Research Council of Canada (NSERC) [], the Leading Edge Endowment Fund [], and the Segal McGill Chair in Molecular Oncology at McGill University (Montreal, Quebec, Canada) []. CHB is also grateful for support from the Warren Y. Soper Charitable Trust and the Alvin Segal Family Foundation to the Jewish General Hospital (Montreal, Quebec, Canada). NVD is grateful for funding from the US-National Institutes of Health [, via grant numbers R01GM114015 and R01GM123247. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.