To monitor the binding mode, we found a dihedral order parameter that separated the 3-iodotoluene binding modes observed during the simulations (see SI); this involved the C1, C5, and I8 atoms of 3iodotoluene and the alpha carbon of VAL111 of T4 lysozyme. This was used to monitor the overall orientation of the ligand in the binding site, e.g. in SI Figure .