In this work, the philicity indices of each atom forming the ester groups of PET4 and PEF4 were calculated, and examined to compare the relative reactivities both at the global and local level. Given the wellestablished dependency of the condensed Fukui functions -formulated in eq. (S11) and eq. (S12) -on the chosen population analysis scheme, four models were selected and compared: the Mulliken, the ChelpG, the Hirshfeld and the minimal basis iterative stakeholder (MBIS) 87 schemes. To compute the condensed Fukui functions, 10 structures were extracted for both PET4 and PEF4 bound to PETase from the unbiased QM/MM MD simulations. For each configuration, the atomic population of each atom involved in the ester group (C, O', O'', Figure ) of the neutral system (𝑄 6 (𝑛)), for the system with 𝑛 + 1 (eq. (S11)) and the system with 𝑛 -1 (eq. (S12)) electrons were calculated. In these two latter cases, the multiplicity of the system was two, and the SCF procedure turned to open shell. The calculations were carried out with ORCA 50 at the B3LYP/def2-TZVP level of theory. The HOMO and LUMO energies were extracted from the calculation for the system with 𝑛 electrons and used to compute the local philicity 𝜔 6 indices as described in eq. ( ) and the local nucleophilicity index (𝑁 6 ) introduced in eq. ( ). The results and associated errors are reported as the mean and standard error of the mean over the 10 configurations sampled for each substrate.