Different simulated systems. We selected different crystal structures in the Protein Data Bank to define the closed, intermediate and Table . Matrix of different simulated systems. Entries in bold denote systems in which the bound ligand is the native ligand of the corresponding starting crystal structure. Throughout this paper, we refer to the bolded elements as native systems and the others as mixed systems. For the sake of brevity, we reference various systems throughout this work in the following manner: [PDB ID]-[ligand name]. This should be interpreted as "the system of [ligand] bound to T4 L99A started from the [PDB ID] structure". As an example, "4w52-benzene system" should be read as "the system of benzene bound to T4 L99A started from the 4w52 structure". open structures for this study. We based our selections on the dominant discrete conformation reported in experiment for each ligand. We arrived at the structure of benzene bound to T4 L99A (PDB ID: 4w52) as our starting structure for the closed state, butylbenzene bound to T4 L99A (PDB ID: 4w57) for the intermediate state and hexylbenzene bound to T4 L99A bound (PDB ID: 4w59) for the open state. We initialized systems for all combinations of these three protein structures (4w52, 4w57 and 4w59) and their three bound ligands (benzene, butylbenzene and hexylbenzene) to generate a total of nine different systems (Table ). We refer to the three systems where the bound ligand is the ligand from the crystal structure as native systems. The remaining six systems where the bound ligand is different from the ligand in the crystal structure are referred to as mixed systems. We set up simulations for all nine systems based on the procedure outlined in the following subsection. For the sake of brevity, we reference various systems throughout this work in the following manner: [PDB ID]-[ligand name] (Table ). This should be interpreted as "the system of [ligand] bound to T4 L99A started from the [PDB ID] structure".