Elevated concentrations cause upright alpha-synuclein conformation at lipid interfaces

Steven J Roeters*, Kris Strunge, Kasper B Pedersen, Thaddeus W Golbek, Mikkel Bregnhøj, Yuge Zhang, Yin Wang, Mingdong Dong, Janni Nielsen, Daniel E Otzen, Birgit Schiøtt, Tobias Weidner*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review


The amyloid aggregation of α-synuclein (αS), related to Parkinson's disease, can be catalyzed by lipid membranes. Despite the importance of lipid surfaces, the 3D-structure and orientation of lipid-bound αS is still not known in detail. Here, we report interface-specific vibrational sum-frequency generation (VSFG) experiments that reveal how monomeric αS binds to an anionic lipid interface over a large range of αS-lipid ratios. To interpret the experimental data, we present a frame-selection method ("ViscaSelect") in which out-of-equilibrium molecular dynamics simulations are used to generate structural hypotheses that are compared to experimental amide-I spectra via excitonic spectral calculations. At low and physiological αS concentrations, we derive flat-lying helical structures as previously reported. However, at elevated and potentially disease-related concentrations, a transition to interface-protruding αS structures occurs. Such an upright conformation promotes lateral interactions between αS monomers and may explain how lipid membranes catalyze the formation of αS amyloids at elevated protein concentrations.

Original languageEnglish
Article number5731
JournalNature Communications
Number of pages12
Publication statusPublished - Sept 2023


  • Humans
  • alpha-Synuclein
  • Parkinson Disease
  • Amides
  • Amyloidogenic Proteins
  • Lipids


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