Lastly, we find multiple states for both mixed systems containing the hexylbenzene ligand. Simulations of hexylbenzene interconvert between the closed and open states when begun from the 4w52 structure (Figure ). Interestingly, the slowest motion of this 4w52hexylbenzene system is an exchange between those two discrete states, but we do not observe any sampling of the intermediate state (Figure ). When begun from the 4w57 structure, simulations of hexylbenzene sample five distinct states (Figure ). Four of the five states are observed in other systems, corresponding to the closed, intermediate and open states as well as the state observed the 4w57-benzene (Figure ) system. The final discrete state falls be- . MSM-resolved states for each native system. We construct MSMs to resolve discrete states based on the slowest processes in each of the three native systems. On top of the density of the concatenated trajectory (gray), we project the frames of simulations of the (A) 4w52-benzene, (B) 4w57-butylbenzene and (C) 4w59-hexylbenzene systems. We color frames based on their MSM-assigned macrostates, keeping macrostate definitions consistent across the different native systems. In the elapsed simulation time (1 µs), native systems are mostly confined to their starting protein conformational states.