Umbrella-like Helical Structure of α-Synuclein at the Air-Water Interface Observed with Experimental and Theoretical Sum Frequency Generation Spectroscopy

Kris Strunge, Tucker Burgin, Thaddeus W Golbek, Steven J Roeters, Jim Pfaendtner, Tobias Weidner*

*Corresponding author for this work

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

Abstract

The misfolding of α-synuclein (αS) into amyloid aggregates is catalyzed by hydrophobic surfaces and associated with severe brain disorders, such as Parkinson's disease. Despite the important role of interfaces, the three-dimensional structure of αS at the interfaces is still not clear. We report interface-specific sum frequency generation (SFG) experiments of monomeric αS binding to the air-water interface, a model system for the important hydrophobic surfaces. We combine the SFG spectra with calculations of theoretical spectra based on molecular dynamics simulations to show that αS, which is an intrinsically disordered protein in solution, folds into a defined, mostly helical secondary structure at the air-water interface. The binding pose resembles an umbrella shape, where the C-terminus protrudes into the water phase, while the N-terminus and the NAC region span the canopy at the interface. In this binding pose, αS is prone to aggregate, which could explain the catalytic effect of hydrophobic interfaces and air bubbles on αS fibrillation.

Original languageEnglish
JournalThe Journal of Physical Chemistry Letters
Volume14
Issue49
Pages (from-to)11030-11035
Number of pages6
ISSN1948-7185
DOIs
Publication statusPublished - Dec 2023

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