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

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.