Ligands 2 and 3 are from the same chemical series as ligand 1 and differ only by methyl substitutions in the terminal phenyl ring. The populations of the binding modes take different amounts of time to converge for the two ligands -10 ns or 5000 iterations for ligand 2 and 40 ns or 20000 iterations for ligand 3. The additional methyl group in ligand 3 decreases the transition rate by almost a factor of seven. Thus, ligands or substituents with bulkier substitutions or large alchemical regions need to be simulated longer to achieve convergence.