The two steering trajectories were combined into a single trajectory and 100 snapshots were extracted from each steering direction, equally sampling the CVs used for steering, using cpptraj. These conformations were used as starting points (or "seeds") for a further 50 ns of equilibrium MD simulations with pmemd.cuda (AMBER22). Trajectories were written out every 10 ps, and simulations were run at 300 K temperature and 1 atm pressure, using Langevin dynamics with γ=2 ps -1 . As discussed in the results section in the case of the I942 restrained systems, some ligand restraints were also maintained during the seeded MD simulations to mimic the effects of additional protein-ligand interactions (Supplementary Table , Supplementary Figure ).