Another potential benefit of the NEQ approach is that it is highly parallelizable which can reduce wall clock time when distributed computing is available. In NEQ calculations, end state simulations can also benefit from enhanced sampling techniques to overcome energy barriers. Intuitively such strategies seem likely to be beneficial. However, recent literature using partial replica exchange MD (an enhanced sampling techique involving exchanges between replicas with modified Hamiltonians) showed no effect of the enhanced sampling. Work in preparation from Gapsys and de Groot also suggests that in some cases, enhancing the sampling of the apo/holo states can drive the system away from the starting crystallographic pose by accumulating force field artifacts and equilibrating in a new free energy minimum which may differ from the experimental one.