Session: Physical Chemistry Poster:

α-synuclein is an intrinsically disordered protein primarily located at the presynaptic terminals in brain tissue. It is known to form oligomers and fibrils which are a key component in the Lewy bodies, the main neuropathological marker of Parkinson’s disease. The fibrillation process of α-synuclein is accelerated in the presence of a lipid interface. The intrinsic disorder of α-synuclein makes it hard to derive a representative protein structure, which hinders efficient study of the fibrillation process. Coupling MD simulations with vibrational SFG spectroscopy allows for investigation of the protein structure of α-synuclein right at a water-lipid interface. Vibrational SFG spectroscopy is a powerful and highly surface sensitive method for observing the vibrational structure of molecules under ambient conditions. Comparison of experimental SFG spectra with simulated SFG spectra based on the MD simulation allows derivation of representative 3D protein structures and their orientation relative to the lipid interface. We used a recently published horseshoe shaped helical structure based on solution NMR as the starting point for the simulations. From the MD-SFG analysis we find that MD trajectories predicting the unfolding of certain residues of the helical starting structure are not in agreement with the observed experimental SFG spectra. At the same time, trajectories predicting an α-helical fold at the membrane interface agree well with the experimental data. This leads us to the conclusion that α-synuclein adopts an ordered helical protein structure at a lipid interface, which could be key in the describing the occurrence and growth of protein fibrils in the brain.

Tobias Weidner

University of Washington

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