MSMs were generated using PyEMMA, with the inter-and intra-Cα-atom distances between the WPD-and E-loop residues of each system (for all pairs of residues that were at least 3 residues apart from one another) used as input features. Simulations from all 5 systems (WT PTP1B and all 4 chimeras) were combined for dimensionality reduction analysis via time-lagged independent component analysis (TICA), meaning all systems share the same time-lagged independent components (TICs). At this point each system was analyzed separately, first by clustering each system using the k-means clustering algorithm to produce between 125-200 clusters/microstates (depending on the system, see Table ). The MSMs generated were then validated by analysis of their implied timescales plots (Figure ), and this was also used to select an appropriate lagtime and number of metastable states for each system.