Polyethylene terephthalate (PET) is the most abundant polyester plastic, widely used in textiles and packaging, but, unfortunately, it is also one of the most discarded plastics after one use. In the last years, the enzymatic biodegradation of PET has sparked great interest owing to the discovery and subsequent mutation of PETase-like enzymes, able to depolymerize PET. FAST-PETase is one of the best enzymes hitherto proposed to efficiently degrade PET, although the origin of its efficiency is not completely clear. To understand the molecular origin of its enhanced catalytic activity, we have carried out a thorough computational study of PET degradation by the FAST-PETase action by employing classical and hybrid (QM/MM) molecular dynamics (MD) simulations. Our findings show that the rate-limiting reaction step for FAST-PETase corresponds to the acylation stage with an estimated free energy barrier of 12.1 kcal mol-1, which is significantly smaller than that calculated for PETase (16.5 kcal mol-1) and, therefore, supports the enhanced catalytic activity of FAST-PETase. The origin of this enhancement is mainly attributed to the N233K mutation, which, although sited relatively far from the active site, induces a chain folding where the Asp206 of the catalytic triad is located, impeding that this residue sets effective H-bonds with its neighboring residues. This effect makes Asp206 hold a more basic character compared to the wild-type PETase and boosts the interaction with the protonated His237 of the catalytic triad in the transition state of acylation, with the consequent decrease of the catalytic barrier and acceleration of the PET degradation reaction.