All systems with the WPD loop closed used protein coordinates from PDB ID 1SUG. All open loop protein conformations were from PDB ID 2HNP, with W179 rotated to match the rotamer in 1SUG using Flare v5 . Both protein conformations included residues 1-282, truncating the α7 helix. Peptide substrate was taken from PDB ID 1EEO. Missing PTP1B residues and all peptide ACE/NME caps were added using In all cases, E97 was modelled as GLH and H214 as HID, due to predicted pK a values of 8.59 and 3.71 respectivelly by propka3 , for PDB ID 2HNP. Additionally D181 was modelled as ASH, and C215 as CYM, to match the proton-donor role of D181 and the coordination of substrate by C215. All system preparation was done through BioSimSpace , except in the case of tethered ligand 3. The ff14SB force field was used for protein residues, with additional phosphate parameters from Case et al. . The ligands were parameterised using GAFF2 and the AM1-BCC charge method. Ligand source PDB IDs and charges are outlined in Supplementary Table . In all cases, TIP3P water was used to explicitly solvate the system as a cuboid box, with 10 distance. Na + ions were added to neutralize the system, and Na + and Cl -ions were added to achieve 150 mM NaCl concentration. All systems were minimized and equilibrated using GROMACS version 2020.2 . Minimisation was carried out over 7500 steepest descent steps. Systems were heated from 0 K to 300 K over 100 ps. Equilibration was performed in the NPT ensemble for an additional 250 ps.