Evolutionary conformational selection is not unique to PETases: de novo designed Kemp eliminases such as the HG3 48 and KE07 series also possess conformational flexible and catalytically important tryptophan side chains in their active sites, the conformations of which are optimized during directed evolution. Similarly, laboratory evolution of an organophsphate hydrolase, serum paraoxonase 1, showed similar conformational effects in key active site residues along the evolutionary trajectory. Similarly to these systems, our results suggest that engineering of PETases with mutations that enable conformational selection of the conserved Trp, such as S/I and the S238A mutation in IsPETase, could lead to predefined active site conformations matching the polymer conformations in PET materials and enable higher catalytic efficiency. Further computational and experimental work is necessary to explore how different Trp conformations enable higher catalytic activity in natural and engineered PETases.