Interaction of α‐Synuclein with Phospholipids and the Associated Restructuring of Interfacial Lipid Water: An Interface‐Selective Vibrational Spectroscopic Study

Abstract

Interaction of α‐Synuclein (αS) with biological lipids is crucial for the onset of its fibrillation at the cell membrane/water interface. Probed herein is the interaction of αS with membrane‐mimicking lipid monolayer/water interfaces. The results depict that αS interacts negligibly with zwitterionic lipids, but strongly affects the pristine air/water and charged lipid/water interfaces by perturbing the structure and orientation of the interfacial water. The net negative αS (−9 in bulk water; pH 7.4) reorients the water as hydrogen‐up (H‐up) at the air/water interface, and electrostatically interacts with positively charged lipids, making the interface nearly net neutral. αS also interacts with negatively charged lipids: the net H‐up orientation of the interfacial water decreases at the anionic lipid/water interface, revealing a domain‐specific interaction of net negative αS with the negatively charged lipids at the membrane surface.

Association of Glial Activation and α-Synuclein Pathology in Parkinson’s Disease

“…The cell membranes and mitochondria are the most common targets of exogenous α-syn oligomers in various types of neuron [30][31][32][33][34][35]. α-Syn oligomers have a high affinity for the lipid bilayer of the cell and organelle membranes, resulting in a disruption of membrane integrity [32][33][34].…”

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

“…Interfaces can catalyze the folding of αS and can stabilize a secondary and tertiary structure. , Misfolding and aggregation into oligomers and fibrils at such interfaces have been associated with serious neurological diseases such as Parkinson’s disease. − Understanding the molecular details of the interaction of αS with surfaces will be an important step toward finding a cure and treatment. The folding of αS at lipid interfaces has been studied with various methods, such as nuclear magnetic resonance (NMR), − electron paramagnetic resonance (EPR), , neutron reflectometry, and sum frequency generation (SFG). − The results paint a picture of the effective catalysis of αS into oligomers and fibrils at lipid surfaces.…”

“…Previous SFG studies have mostly focused on vibrational modes in the interfacial environment, either water or lipid vibrations, and showed that αS was surface active and perturbed the interfacial environment. , αS has been probed directly in the amide I region at lipid membranes, revealing that the structure was characterized by a α-helical N-terminus lying in the lipid–water plane. It was also found that αS becomes less flat and more solvated with an increasing concentration …”

Umbrella-like helical structure of alpha-synuclein at the air-water interface observed with experimental and theoretical sum frequency generation spectroscopy

“…[4][5][6][7] Understanding the molecular details of the interaction of aS with surfaces will be an important step towards finding a cure and treatment. The folding of aS at lipid interfaces has been studied with various methods, such as nuclear magnetic resonance (NMR) [8][9][10][11][12][13] , electron paramagnetic resonance (EPR) 8,11 , neutron reflectometry 14 and SFG [15][16][17] . The results draw a picture of effective catalysis of aS into oligomers and fibrils at lipid surfaces.…”