C2, host: C9, Figure ) that can represent different orientations of the guest and the distance between the guest and host sampled in the simulation. We picked 4 states of which three (States 1-3, Figure ) were the most populated and represent different orientations of the guest in the cavity. The remaining one (State 4, Figure ) was a conformation where the guest is right at the entrance of the host pocket. Position restraints with a spring constant of 20 kcal/mol/Å 2 were applied on the heavy atoms of the guest and two carbon atoms (C33 and C34, Figure ) on the host. Three replicates of additional BLUES simulations were performed for each starting point and each replicate included 5000 iterations NCMC moves.