The E. coli Adenosine Kinase (ADK) has two biologically relevant states. Substrate binding will trigger the protein to switch between an open and a closed state. The two moving domains are referred to as the "lid" (red) and the nucleotide monophosphate ("NMP") binding domain (blue), which moves in a manner analogous to folding and unfolding a multitool knife, with the core domain (white) acting as the anchor point (Figure ). The experimental structures of these two states are available in the Protein Data Bank, with the identifiers 1AKE (closed) and 4AKE (open), respectively. A commonly used method to characterize this motion is by measuring the angles between the core domain and both the lid and the NMP domain, named lid angle and NMP angle respectively (Figure ). The first step of structural generation involves generating hypotheses using reduced MSA AlphaFold2. We generated 640 structures with an MSA depth of 8:16, 640 structures with an MSA depth of 16:32, and 25 structures with full MSA, which utilizes up to 512:5120 sequences. These structures can cover a modest portion of the intermediate regions between the open (4AKE) and closed (1AKE) states in the Lid-NMP angle space (upper left, Figure ). 7 cluster centers (red circles, Figure ) were picked automatically among the The number of states found by SPIB from the trajectory is controlled by a key hyperparameter: the time lag ∆t. SPIB tries to find the minimal information that is needed to predict the future states of the system after ∆t. Longer time lags will average out the faster dynamics of the system, leaving only the typically slower large conformation changes under the radar. Consequently, as ∆t increases, the number of states SPIB can identify decreases (Figure ), since faster dynamics are ignored leaving larger conformational changes with slower dynamics to be recognized. In our work, we used a ∆t = 10 ns. While the number of state changes, the quality of of the state classification is agnostic of choice ∆t within a wide range, as it does not alter the underlying latent space structure but instead functions as a control for granularity of the labeled states. A more detailed discussion is in the Supplementary Information and Figure . A-loop and DFG motif of Human DDR1 kinase DDR1 is a protein kinase characterized by two major conformational elements of interest.