Figure 1. Design of α-syn seeding inhibitors.

(A) Structure-based design of α-syn aggregation inhibitors. The NACore protofilament is a dual β-sheet homo-steric zipper (upper left) (PDB ID: 4RIL). The inhibitors (cyan) cap the protofilament at one or both ends. S37, S61 and S62 are shown here to bind to the end with lower binding energy and S71 is shown to bind the only end to which it is predicted to bind. (B) Binding energies (REU, Rosetta energy units) of the four inhibitors calculated by Rosetta suggest that S37, S61 and S62 bind to both top and bottom interfaces whereas S71 is predicted to bind only to the bottom of the protofilament. Shape complementarities (Sc) of all four inhibitors with the end of the protofilament are high.