Intrinsically Disordered to Stable and Reversible α-Helical Conformational Transition of α-Synuclein in a Neat...

α-synuclein (α-Syn), an intrinsically disordered protein associated with Parkinson's disease, exhibits a high propensity for aggregation under physiological and in vitro conditions, even at low concentrations. This necessitates its storage in the lyophilized form at ≤ -20 °C. In this work, we demonstrate that dispersing native α-Syn in an aqueous solution of poly(ethylene glycol)(PEG)-based polymer surfactant (PS), followed by lyophilization, forms a viscoelastic material at room temperature, in which α-Syn adopts a highly stable and reversible α-helical secondary structure. Solid-state NMR analysis reveals that helix formation involves alanine, threonine, and valine residues, predominantly within the N-terminal and NAC regions. Interestingly, small-angle X-ray scattering (SAXS) studies indicate that a neat PS matrix exhibits a distorted lamellar mesophase; however, it becomes ordered upon α-Syn incorporation. All-atom MD simulations show that PS hydrophobic domains self-assemble into "nematic-like" structures that selectively interact with the hydrophobic residues in α-Syn. These findings establish polymer-driven strategies for long-term storage and structure-function stabilization of various therapeutic proteins.