Wide-Line NMR Melting Diagrams, Their Thermodynamic Interpretation, and Secondary Structure Predictions for A30P and E46K α-Synuclein

Parkinson's disease is thought to be caused by aggregation of the intrinsically disordered protein, alpha-synuclein. Two amyloidogenic variants, A30P, and E46K familial mutants were investigated by wide-line H-1 NMR spectrometry as a completion of our earlier work on wild-type and A53T alpha-synuclein (Bokor, M. et al. WT and A53T alpha-synuclein systems: melting diagram and its new interpretation. Int. J. Mot Sa. 2020, 21, 3997). A monolayer of mobile water molecules hydrates A30P alpha-synuclein at the lowest potential barriers (temperatures), while E46K alpha-synuclein has here third as much mobile hydration, insufficient for functionality. According to wide-line H-1 NMR results and secondary structure predictions, E46K alpha-synudein is more compact than the A30P variant and they are more compact than the wild type (WT) and A53T variants. Linear hydration vs potential barrier sections of A30P alpha-synuclein shows one and E46K shows two slopes. The different slopes of the latter between potential barriers E-a,E-1 and E-a,(2) reflect a change in water-protein interactions. The 31-32% homogeneous potential barrier distribution of the protein-water bonds refers to a non-negligible amount of secondary structures in all four alpha-synuclein variants. The secondary structures detected by wide-line H-1 NMR are solvent-exposed alpha-helices, which are predicted by secondary structure models. beta-sheets are only minor components of the protein structures as three-and eight-state predicted secondary structures are dominated by alpha-helices and coils.

Automated summary

Parkinson's disease is caused by aggregation of the protein alpha-synuclein, and the variants A30P and E46K have different hydration properties and compactness compared to the wild-type and A53T variants. The E46K variant has a more compact structure and altered water-protein interactions.