Binding studies, including in L99A, are typically done on much shorter timescales than those studied here. Thus, it is vital for researchers running such studies to have an idea of the relevant timescales for protein conformational sampling, and ensure that (a) they are using the appropriate protein structure(s) for their ligand, or (b) they are somehow enhancing sampling of protein conformational transitions, or (c) they diagnose the quality of protein sampling. Given that it is relatively common for structure-based design studies to uncover multiple distinct protein conformations upon binding of different ligands, it may be possible to anticipate some of these conformational changes. However, timescales for transitions between relevant protein conformations might be slow and uncharacterized, in which case researchers need to be cautious. We argue that it may be necessary to further develop and employ enhanced sampling methods for dealing with protein conformational changes. Lastly, we make all files necessary to reproduce our trajectories freely available. We also include the code used for analysis so that researchers can access our state analyses. Additionally, one potential follow-up of this work would be to investigate which specific structural features in the protein are best associated with classification into the various discrete states. To aid such follow up work, we include snapshots of structures along various points in the TICA surface should researchers wish to analyze this data in the Supporting Information (Figure ).