and avidin were solvated with 6662 and 11919 water molecules, respectively. The alanine octapeptide system was solvated with 7918 water molecules. The cutoff for the MM interactions was 8.0 Å, in every case. The cutoff for ML/MM and QM/MM interactions was 18.0 Å, for the simulations of phenol and 15 Å, for all the other systems. We employed GAFF 69 parameters when modeling phenol, oxazole-4-carbaldehyde and both ligands at the MM level, using RESP 70 charges from HF/6-31G* electron densities. The alanine peptides and the two proteins were modeled using the ff19SB 71 force field. Lennard-Jones parameters used were the ones corresponding to each MM force field. In the case of the avidin complex the starting structure corresponded to the Protein Data Bank Identifier 1AVD, for the FKBP complex it was 1FKH. The initial ligand structures were achieved in both cases by simply removing atoms from the original ligands, this approach is validated by the high structural similarities between the ligand-analogue pairs (both analogues being smaller than the ligands) and has been used before for these same complexes. Missing hydrogen atoms were added in Modeller, ensuring the ligand remained neutral. All simulations were performed with our ML/MM and ANI codes integrated in AmberTools24, and the QM/MM simulations employed the existing interface with Gaussian09. The system preparations were made with LEaP, antechamber, and parmchk2 77 tools from AmberTools24. Visualizations of molecular dynamics and molecular drawings were created using VMD (version 1.9.3) and the Chemical Sketch Tool available on the RCSB Protein Data Bank website.