One implication of this finding is that previous work looking at the transitions between states for this system may have used incorrect state definitions and potentially miscounted transitions and misdiagnosed the extent to which protein conformational transitions are adequately sampled on simulation timescales. It may be worth revisiting this work and applying these TICA-based state definitions to evaluate how much enhanced sampling methods are able to accelerate transitions. Furthermore, we believe our approach of using slow system dynamics to define individual states could be extended to other systems where there are known conformational changes in response to a congeneric series of ligands. Examples of known systems with such behavior include the heat shock protein 90 (HSP90) and the human estrogen receptor alpha (ERα). This approach could especially be useful in systems where there may not necessarily be reference crystal structures for each discrete state, since in such cases an RMSD-based analysis is not possible.