WT and A53T α -synuclein systems: Melting Diagram and its new interpretation

Abstract Parkinson’s disease is connected with abnormal α -synuclein ( α S) aggregation. Energetics of potential barriers governing motions of hydration water is examined. Information about the distributions and heights of potential barriers is gained by a thermodynamical approach. The ratios of the heterogeneous water-binding interfaces measure proteins’ structural disorder. All α S forms possess secondary structural elements though they are intrinsically disordered. Monomers are functional at the lowest potential barriers, where mobile hydration water exists, with monolayer coverage of mobile hydration. The α S monomer contains 33% secondary structure and is more compact than a random coil. A53T α S monomer has a more open structure than the wild type. Monomers realize all possible hydrogen bonds. Half of the mobile hydration water amount for monomers is missing in α S oligomers and α S amyloids. Oligomers are ordered by 66%. Mobile water molecules in the first hydration shell of amyloids are the weakest bound compared to other forms. Wild type and A53T amyloids show identical, low-level hydration, and are considered as disordered to 75%. Statement of Significance Aggregation of α-synuclein into oligomers, amyloid fibrils is a hallmark of Parkinson’s disease. A thermodynamic approach provides information on the heterogeneity of protein-water bonds in the wild type and A53T mutant monomers, oligomers, amyloids. This information can be related to ratios of heterogeneous water-binding interfaces, which measure the proteins’ structural disorder. Both α-synuclein monomers are intrinsically disordered. The monomers nevertheless have 33% secondary structure. They are functional as long as mobile water molecules surround them. They realize every possible H-bonds with water. Oligomers are like globular proteins with 66% ordered structure. Amyloids are disordered to 75% and are poorly hydrated with loosely bound water. Their hydration is identical. Oligomers, amyloids have only half as much hydrating mobile water as monomers.