The seeded MD trajectories were featurised using cpptraj . The features used were WPD loop (residues 178-184) backbone RMSD to PTP1B with WPD loop closed (PDB ID 1SUG), and P loop (residues 214-219) RMSD. All MSM model buiding was done using PyEMMA version 2.5.7 . All system data was pooled together, and k-means clustering (100 cluster centers) was used to define microstates. Implied timescales were calculated using a range of lag times between 1 and 3000 steps (10 ps to 30 ns). MSMs were generated with a lag time of 2000 steps (20 ns) in all cases. PCCA analysis of the reference system was performed to define two macrostates, assigning the macrostate with lowest RMSD as the active state. The clusters not sampled by the reference system were assigned to the inactive state. When clusters were not sampled by a particular system, they were assigned 0% stationary probability manually.