AbstractHerein, we examine computationally the binding and hydrolysis reaction of the MMP‐2 enzyme with two peptide substrates selected by the enzyme from a phage peptide library. Molecular dynamics simulations of the Michaelis complexes (25 ns) allow us to characterize the main enzyme/substrate contacts. Subsequently MM‐PBSA calculations using independent trajectories for the complexes and the free substrates provide relative binding energies in good agreement with the experimental KM results. Computational alanine scanning analyses of the enzyme/substrate interaction energies confirm the relevance of the P3, P2, and P1′ side chains for ligand binding. Finally, the hydrolysis of both peptides taking place at the MMP‐2 active site is explored by means of hybrid quantum mechanical/molecular mechanics calculations. The computed reaction mechanisms result in rate‐determining energy barriers being in consonance with the experimental kcat values. Overall, the computational protocol seems to