The NEQ approach does not offer a free lunch in the sense that the relevant conformations still need to be sampled in the end-state ensembles . Compared to the more popular free energy perturbation (FEP) series of methods , though, it does offer several advantages in terms of computational efficiency. Namely, such sampling needs to be performed only for physical end-states and can be done with plain molecular dynamics or, if desired, it can also be augmented with enhanced sampling methodologies in a straight forward manner . Secondly, the out-of-equilibrium portion of the approach, which accounts for the majority of the compute time, is highly parallelizable, requiring no information exchange between individual simulations, unlike modern FEP approaches with replica exchange . Furthermore, the NEQ approach allows for initialization of the two end-states with the distinct apo and holo protein structures, which facilitates obtaining reliable equilibrium ensembles for the cases where experimental structures are available. For an equilibrium FEP approach, incorporation of different conformers in a single ∆G estimation would require decision on the mixing rule for seeding the starting structures and potentially Hamiltonian replica exchanges would be needed to achieve convergence. Finally, when comparing different ligands, protein mutations, or conformational states NEQ allows for reuse of existing equilibrium sampling of end-states, e.g. the same apo state can be used for assessing affinities of different ligands.