Transient Secondary and Tertiary Structure Formation Kinetics in the Intrinsically Disordered State of α-Synuclein from Atomistic Simulations

Timo Graen, Reinhard Klement, Asaf Grupi, Elisha Haas, Helmut Grubmüller

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

In the absence of a stable fold, transient secondary structure kinetics define the native state of the prototypical and pharmacologically relevant intrinsically disordered protein (IDP) α-Synuclein (aS). Here, we investigate kinetics preventing ordering and possibly pathogenic β-sheet aggregation. Interestingly, transient β-sheets form frequently at sub μs time scales precisely at the positions observed in aS amyloid fibrils. The formation kinetics competes with rapid secondary structure dissociation rates, thus explaining the low secondary structure content. The fast secondary structure dissociation times are very similar to the dynamics of tertiary structure rearrangements. These findings suggest that the fast dissociation kinetics slows down conformational selection processes for aS aggregation, which may be a general mechanism controlling the aggregation kinetics of IDPs.

Original languageEnglish
Pages (from-to)2507-2511
Number of pages5
JournalChemPhysChem
Volume19
Issue number19
Early online date25 Jul 2018
DOIs
StatePublished - 5 Oct 2018

Bibliographical note

Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • alpha-synuclein
  • intrinsically disordered protein
  • molecular dynamics
  • protein models
  • structural dynamics

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