PLoS Computational Biology (Mar 2019)

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

DOI
https://doi.org/10.1371/journal.pcbi.1006859
Journal volume & issue
Vol. 15, no. 3
p. e1006859

Abstract

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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.