In silico investigation of the interaction between α-synuclein aggregates and organic supramolecular assemblies†

α-Synuclein (αSYN), and its tendency to self-aggregate, plays an important role in the development of Parkinson's disease (PD). αSYN aggregates are characterized by a stacking of αSYN chains and an interaction between the stackings to form dimer-like structures. The stability of these supramolecular assemblies is ensured by the presence of numerous residues that adopt “β-strand” and then “β-sheet” conformations, implying multiple interactions within and between the chains of αSYN. Following our previous study on the ability of small organic molecules to form columnar supramolecular assemblies (organic nanotubes, ONs) [Le Bras, L.; Dory, Y. L.; Champagne, B. Computational prediction of the supramolecular self-assembling properties of organic molecules: the role of conformational flexibility of amide moieties. Phys. Chem. Chem. Phys., 2021, 23, 20453–20465], we propose here to unravel the ability of these ONs to interact with αSYN aggregates. More than an interaction, we expect the organic molecules to avoid the complete aggregation process and ideally to induce destabilization of the stacking. Both molecular dynamics simulation and quantum mechanical-based calculations are used to identify the key parameters of the interaction and the resulting (de)stabilization of the assembly.