The offset introduced by the removal of orientational restraints may be reduced or re-moved through the use of the Hamiltonian-replica exchange (HREX) method. This is because in the fully decoupled state, there are no barriers to orientational rearrangements, and HREX has been found to improve sampling when the barriers in configurational space are low in at least one state. This allows free sampling of varied orientations, and mixing of these into the intermediate λ states using HREX may improve orientational sampling.