Enzyme-reactant complex. The crystal structure of IRAP monomer in the catalytically active closed conformation with the phosphinic acid ligand was obtained from the Protein Data Bank (PDB ID 5MJ6). The missing loop 640-648 was taken from an AlphaFold model and a disulfide bridge was created between cysteines 828 and 835. All crystal water molecules were retained, whilst the ligand, carbohydrates and bromide ions present in the PDB were removed. The protonation states of all titratable residues under physiological conditions were assigned with the H++ server. In the absence of a crystal structure of the complex between the enzyme with oxytocin and angiotensin IV, each peptide was docked separately near the zinc ion preserving hydrogen bonding with the GAMEN loop. Angiotensin IV was docked using the HPEPDOCK server while the cyclic oxytocin peptide was docked using GOLD. In MD simulations, the AMBER ff14SB force field was used for protein residues, and a 12-6 Lennard-Jones potential was used to model a divalent zinc ion (which was treated QM in QM/MM simulations, see below). The obtained E-R complexes were solvated with a truncated octahedron of TIP3P water molecules 57 with a 10 Å distance between the edge of the initial solvation cell to the edge of the solvent box, using periodic boundary condition (PBC). The systems were neutralized by adding Na + counterions.