The Cα atom root mean square deviations (RMSDs) and the first two side chain dihedral angles of W50 (χ1 and χ2) that were required to determine the per frame target variable value for the simulations of PTP1B and the two KE07 variants were determined using CPPTRAJ. A shell script was written to determine the per frame conformational state given the RMSD value (see the Supplementary Information). In the case of simulations of the PDZ3 domain, the frames were classified simply by if they were from the peptide bound or unliganded simulations.