The selection of problems was made based on popular applications of QM/MM simulations, covering for example studies in aqueous solution, 60,61 spectroscopy 62,63 and drug discovery. Specifically, we tested our ML/MM model in the following systems in aqueous solution: (i) The solvation structure and vibrational spectra of phenol; (ii) torsion free energy profile of oxazole-4-carbaldehyde (also known as 4-oxazolecarboxaldehyde); (iii) The 2-dimensional free energy surface of the Ramachandran angles of the capped alanine dipeptide; and (iv) two protein-ligand complexes: enzyme FKBP12 bound to an FK506 analogue and avidin 67 bound to a biotin analogue; the existence of both complexes is supported by experimental data, and we chose these analogues instead of the natural ligands for being neutral compounds. The ML subsystem was integrated by the solute in cases (i) to (iii), and by ligands in the case of the protein-ligand complexes.