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

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

Author information

1
University of Victoria -Genome British Columbia Proteomics Centre, Vancouver Island Technology Park, Victoria, British Columbia, Canada.
2
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
3
Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Quebec, Canada.
4
Departments of Pharmacology, and Biochemistry and Molecular Biology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, United States of America.
5
Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
6
Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

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.

PMID:
30917118
PMCID:
PMC6453469
DOI:
10.1371/journal.pcbi.1006859
[Indexed for MEDLINE]
Free PMC Article

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