The results presented are averages from these simulations. During every PDLD/S-LRA simulation, the linear response approximation (LRA) calculation was executed on ten different configurations sampled throughout the trajectory. The binding energies for the various poses are presented in Table . It is evident that the binding energies across different configurations are relatively similar, with notable exceptions being the surface, different layer (Re), and same layer (Re) poses. These values are in close alignment with the experimentally observed binding energy. This suggests the possibility of multiple binding sites. However, it also highlights the challenge of identifying the optimal binding pose due to the extremely flat surface of the fibril and the lack of distinct catalytic pockets. Nevertheless, the binding energies are in excellent agreement with the observed value of -3.34 kcal•mol -1 , particularly for the poses with different layer (Si), the same chain (Re), and the same layer (Si), which have binding energies of -3.23, -3.40, and -3.42 kcal•mol -1 , respectively (refer to Fig. and). For the downstream EVB free energy calculations, the same chain (Re) pose was selected due to the proper orientations of the catalytic residues, Ser118 and His117, facilitating the PT-NA process (see Fig. ). This is in contrast to other potential poses, where the proton of Ser147 is oriented away from the N δ of His117 (Fig ). It is worth noting that we also investigated the reaction mechanism with the same layer (Si) pose but found its free energy profile to be kinetically unfavorable with EVB activation barrier of over 25 kcal•mol - -2.82 a From the experimental 𝐾 𝑚 measured at pH 7.4, we approximated the binding energy using equation ∆𝐺 𝑒𝑥𝑝 = -𝑅𝑇𝑙𝑛𝐾 𝑚 = -3.34.