Our results show that these substitutions increase flexibility of both active site loop regions harboring key catalytic residues, and the conformational plasticity of the conserved tryptophan within the W-loop. Notably, while all of the experimentally determined tryptophan conformers are accessible for all enzymes, the S/I substitution appears to facilitate population shifts to and from conformer A, as well as other conformations, such as a 180º side chain rotation that has not been observed in any solved crystal structures of PETases. Overall, our simulations provide evidence for a dynamical origin for the enhanced catalytic activity of the S/I variants, affecting both loop dynamics and the conformational plasticity of the tryptophan.