The RAMD literature suggests that ligands with simulation times shorter than 100 ps should have their force constant decreased and postulates that ligands with experimental times shorter than 10 s should not be run with the same force constant as those with pharmacologically relevant residence times. Furthermore, it is common practice to increase the number of RAMD replicas when ligands have high variance in their simulation times. Upon investigating the RAMD fit for T4 Lysozyme, we found that 3 of the ligands had very similar RAMD simulation times leading to a Spearman ρ of only 0.26 while all ligands had large standard error (full details in Supporting Information). Based on these results we reduced the force constant from 15 kcal/mol/Å 2 to 5 kcal/mol/Å 2 and doubled the number of RAMD replicas to 60. It should be noted that Nunes-Alves et al. previously studied this system and reduced their force constant by a similar factor compared to RAMD work on longer-lived complexes. Given the similar experimental timescales of Beta Trypsin ligands and their RAMD simulation times near or below 100 ps, we also reran these simulations with a force constant of 5 kcal/mol/Å 2 .