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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.

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


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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