To address this, we utilized an NMR-determined crystal structure (PDB entry: 6NZN), with ten submitted conformers) as a template to search for potential binding modes. Since the catalytic residues are exclusively located at the peptide termini as mentioned above, we conducted an automatic docking targeting the termini of the fibril across all ten conformers. These docked structures were then manually adjusted to produce suitable starting points for subsequent binding and reaction energy profile calculations. Notably, we explored several configurations of our substrate and binding poses during the docking process, namely, the Re and Si faces of the carbonyl carbon of p-NPA binding in the outer surface, same chain, same layer, and different layer on the amyloid fibril (see Fig. ). To further validate our findings, we employed the PDLD/S-LRA-2000 method to determine the binding energy for each docking mode. For each mode, we conducted five distinct simulations, each initialized with different structures sampled by the ENZYMIX force field.