Protein and Coupled Solvent Dynamics of Oligomeric and Fibrillar α-Synulein

α-Synuclein (αS) is a protein that has an unspecified functional role in neurotransmitter release in brain neurons, and dysfunction associated with Parkinson's disease (PD).¹ Monomeric αS is an intrinsically-disordered protein (IDP). Toward understanding the role of protein and coupled solvent dynamics in αS function and dysfunction, our established electron paramagnetic resonance (EPR) spin probe (TEMPOL) methodology was applied.^2,3,4 Controlled-temperature ice-boundary confinement in frozen aqueous solutions of induced oligomeric and pre-formed fibrillar αS was used to localize TEMPOL to probe solvent phases specifically associated with αS. TEMPOL mobility in the presence of αS shows two distinct components at temperatures from 220 – 265 K, as for soluble globular proteins,⁵ but with dramatically higher fluidity. The temperature-dependence of the spin probe rotational correlation times and component weights, and hysteresis in these parameters for directional temperature change, are interpreted in terms of a high-fluidity, confinement-resistant aqueous-C-terminal protein domain (residues 96-140) mesophase. The results are relevant to the function of αS under high confinement conditions in the neuron presynaptic terminal region, and dysfunction, that involves oligomer and fibril permeation of phospholipid bilayer membranes.