The Supporting Information is available free of charge on the ACS Publications website at (details) and includes a PDF file containing SI Figure (showing work distributions for rotating toluene in lysozyme as a function of the amount of NCMC relaxation), Figure (showing the work standard deviation for toluene in lysozyme as a function of the amount of switching), Figure (showing the dihedral progress coordinate used for 3-iodotoluene), Figure (showing the estimated MSM transition matrix for toluene in lysozyme), Figure (showing acceptance of NCMC vs standard MC move proposals as a function of dihedral angle/binding mode, given a fixed ensemble of MD snapshots), and Figure (showing the acceptance probability for toluene in water as a function of the amount of switching); a .tar.gz file containing a set of scripts for running MD and MD/MC and MD/NCMC, simulation run input files for the GROMACS simulations described here, scripts for the OpenMM simulations described, input topology and coordinate files for all simulations, a README.md file detailing organization, and scripts for MSM construction and PCCA analysis as noted in Methods, as well as a copy of the BLUES code used to generate the data presented here.