MSMs were built for all of the systems, using the k-means cluster centers as states to transition between. From state transition probabilities, the equilibrium probabilities of each state were computed. When not visited by a particular system, states were manually assigned a stationary probability value of 0. Perron Cluster-Cluster Analysis (PCCA) of the reference MSM was used to further cluster the states into two macrostates, referred to as "active" and "inactive" based on the RMSD of the loops . The metastable state with lower RMSD values corresponds to the active state. The procedure was repeated a hundred times, using the initial micro-and macrostate definitions, to generate probability distributions for observing active states for each system (Figure ).