In general, the initial test systems were prepared from crystal structures, retaining crystal waters and discarding all other non-protein and non-ligand atoms. Details of initial structure preparation for individual systems are given in Section S3 and the rationale for system selection is given in Section 4.1. Alternate atom locations with the greatest occupancy were selected (or the A state, if occupancies were equal). Missing atoms were added using pdb4amber. The protonation states of all residues were assigned using H++ (version 3.2). Proteins and crystal waters were parameterised with the AMBER ff14SB and TIP3P force fields using antechamber 22.0. Ligands were protonated using Open Babel (version 3.0.0) and parameterised with OpenForceField 2.0.0 and AM1-BCC partial charges through BioSimSpace (version 2023.0.0). The protein-ligand complexes and free ligands were solvated with TIP3P water and 0.15 M of NaCl in rhombic dodecahedral boxes, ensuring a minimum distance of 15 Å between the solute and the box edge. The Cyclophilin D systems were taken from the "abfe 2fs" input supplied by Alibay et al. (GAFF2 with AM1-BCC partial charges, ff99SB-ILDN, and TIP3P force fields). These were used with two minor modifications -the ligands were extracted and reparameterised with GAFF2.11 and AM1-BCC partial charges using antechamber 22.0 to avoid issues with non-integer charges, and the boxes were expanded to rhombic dodecahedral boxes with a minimum solute-box edge distance of 15 Å to allow the use of a 12 Å cutoff for reaction-field electrostatics.