We initialized BLUES simulations with 5 replicates. For each iteration, 1 NCMC move and 1000 MD steps were executed with hydrogen mass repartitioning scheme with 4 fs integration time step . Each NCMC move was executed for 4400 steps (400 steps between lambda 0.0 to 0.2, 3600 steps between lambda 0.2 to 0.8, and 400 steps between lambda 0.8 to 1.0). This approach increased move acceptance in previous work . 3900 iterations BLUES simulations were performed for each replicate. After checking collected data, we found (1) the ethyl groups orientations changed with the guest orientation in the pocket and (2) the guest unbound in in all 5 replicates. These results indicated the difficulty of adequate sampling of these ethyl groups and restraints were needed for both efficient sampling and keeping the host-guest in the bound state.