The use of origin-dependent position restraints requires careful evaluation of the Hamiltonians of the origin-dependent stages (stages 4 and 5) with the trajectories of the origin-independent stages (stages 1 through 7, except stages 4 and 5) for correct MBAR calculations. Without special care, the Hamiltonian of an origin-dependent stage evaluated with the trajectory of an origin-independent stage will result in an incorrectly high potential of the restraints. This will be so even if the configuration of the binding site does not significantly change, because the absolute positions of the heavy atoms in the origin-independent trajectory will shift and/or rotate across the unrestrained simulation.