Two repetitions for BLUES were run for 10,000 iterations. Between each NCMC move, we conducted at least 1000 steps (2ps in total) of MD before the state of the Val111 χ 1 dihedral was assessed, with increments of 2ps of MD added as needed until the rotamer fell within the biased dihedral range, as described previously. Each NCMC move was executed for 2200 steps with nprop = 3 ; nprop is a parameter in BLUES that adds additional NCMC propagation steps during the middle phase (lambda 0.2 to 0.8) of the NCMC switching protocol. The final result was that in this case, 200 steps were used between lambda values 0.0 to 0.2 (1000 steps per lambda unit), 1800 steps were used from lambda 0.2 to 0.8 (3000 steps per lambda unit), and 200 steps were used in lambda 0.8 to 1.0 (1000 steps per lambda unit). This approach increases the rel-ative number of NCMC steps used during the alchemical cycling of the steric interactions; previously we have found that this increases move acceptance of ligand rotations in BLUES.