MD simulation of LIN5001 bound to fibrils consisting of T-A-K.

We devised a minimal model of an LIN5001 binding site on a prion fibril that captures the main interactions at the atomic level of detail. The model consisted of eight 3-residue peptides (S-A-K) arranged in a parallel in-register β-sheet. The initial coordinates were derived from the HET-s NMR structure (PDB code 2LBU), in which the docked Congo red lies within a groove that is perpendicular to the solenoid β-sheet. The groove originates from parallel β-strands of alternating S227-A228-K229 and S263-V264-E265 segments where the backbone atoms of the central residues (that is, A228 and V264) form the floor of the groove and the side chains of residues S227/ S263 and K229/E265 represent the walls. To generate the initial parallel in-register β-sheet arrangement of eight S-A-K peptides, residues V264 and E265 were mutated into Ala and Lys, respectively, using visual molecular dynamics. The LIN5001 were docked manually according to the binding mode of Congo red.