We clustered the MD snapshots based on the RMSD of the gorge residues to obtain diverse but biologically relevant conformations of the s-glycoprotein. The obtained clusters are ranked in terms of their populations. The most populated cluster, s1, dominated almost the entire second half of the trajectory (SI-Figure ). The mean RMSD of the gorge residues in this cluster was 3.46 ± 0.13 Å, which is close to the average value for the entire simulation (3.66 ± 0.38 Å) (SI-Figure ). Conversely, the least populated cluster (s7) had RMSD values indicating that it remained close to its starting structure (1.62 ± 0.69 Å). Representative structures of the clusters (SI-Figure ) and their tunnels (SI-Figures and) were also obtained, enabling further analysis (SI-Figure ). CaverDock calculations were performed using representative structures of the 5 most populated clusters in the same way as described for the cryo-EM structure (Figure ). Each tunnel had a unique profile, but in all cases, the narrowest section was in the deepest region of the tunnel, close to the S2 subunit. The vast majority of the ligands have their lowest binding energies in this region (Figure ). The sole exception is the most populated state, s1, for which the majority of the ligands have their lowest binding energies in the middle of the tunnel (Figure ). The tunnel in this state is slightly wider than in the other states, making it difficult for ligands to form contacts with all three monomers. The tendency for the binding energies of drugs to be lowest immediately before or after a bottleneck was seen for all states.