Originally, we used many pairwise-distances as an order parameter when constructing the MSM to identify toluene's binding modes (Sec 2.4). Once those binding modes were identified however, further analysis found that a simple 1-dimensional progress coordinate could separate and identify them. To monitor the binding mode of toluene in the cavity, we picked a dihedral angle which clearly discriminates between toluene's four distinct binding modes. Specifically, toluene's binding mode was monitored via calculation of the dihedral formed by the alpha carbon of ARG118 and the C1, C5, and C7 atoms of toluene (Figure ). These angles were then used for construction of histograms to monitor populations of the observed binding modes and the number of transitions between binding modes. The populations of the different binding modes were monitored by using the following different bin boundaries [-⇡, -1.5), [-1.5, 0), [0, 1.5), [1.5, ⇡). We assigned the following state labels according to the bin locations: [-⇡, -1.5) is B1, [-1.5, 0) is A1 [-1.5, 0) is B2, and [1.5, ⇡) is A2, where the A labels correspond to the crystallographic binding mode and B labels correspond to an in-plane rotated binding mode. To determine the uncertainty in the computed population as a function of simulation time, the populations of each binding mode were determined using fractions of the total simulation data in a blocking approach. The uncertainty in the computed populations were determined based on breaking each 10% of the simulation into a set of smaller blocks. The number of blocks used was the amount that maximized the standard deviations of the populations between blocks. For NCMC/MD this was 8 blocks. For MD and MC/MD, the standard deviation in the mean across blocks via bootstrapping failed to reach a maximum even with only one block per 10% of the simulation. The error bars in the plots of the MD and MC/MD simulations are shown based on one block per 10% of the data, but are likely to severely underestimate the true error.