The T4 lysozyme binding site is relatively simple, and most ligands have only a small number of stable/metastable binding modes (e.g. here, M in Figure is typically two to a few). This limits any efficiency gains our method might provide in this site relative to the efficiency which could be expected compared to conducting separate binding free energy calculations for each stable binding mode. However, biological binding sites can have far more metastable binding modes (e.g. ). Thus, our main focus in this work is to compare the efficiency of different approaches for sampling ligand binding modes in lysozyme, and not to benchmark of our method to absolute binding free energy calculations.