Here, to compare the efficiency of our NCMC approach, BLUES, to that of brute force molecular dynamics and MSMs, we applied BLUES to the T4 lysozyme/toluene system. We applied the NCMC protocol of thermodynamic perturbation with random rigid-body ligand rotations (as described in Section 2.1.4) to observe the protocol's efficiency in sampling binding mode interconversions. The NCMC protocol was applied over 5000 iterations, each consisting of 10000 MD steps separated by NCMC move proposals consisting of turning off and restoring ligand interactions over 10000 steps, with random rotations while the ligand is noninteracting.