Overlapping work distributions don't guarantee reliable free energy estimates. Overlapping work distributions are a necessary but not sufficient requirement to obtain reliable free energy estimates. Consider for example a system where slow side chain rearrangements occur upon ligand binding. If this rearrangement is neither sampled in the equilibrium end state simulation nor in the fast switching transitions, the work distributions might overlap well. Computed free energies, however will not be correct, because the contribution of structural rearrangement in the binding site is not accounted for (Sec. 5.3.2, Figure ). Running independent replicates helped assess these issues in this work. Phase space overlap measurements can serve as a diagnostic metric and have been examined fairly extensively for equilibrium calculations. Even though sufficient overlap of the potential energy distributions of neighboring λ states is crucial to obtain an unbiased estimate, it is important to remember that overlap alone does not guarantee that sampling is adequate. 4.5. We compared the EQ and NEQ approaches based on convergence of computed free energy differences where possible. Since the two approaches start their simulations from systems parameterized and prepared in the same way, the calculated free energy differences should converge to the same value when sampling is sufficient. In order to assess which method converges faster, we looked at how the cumulative ∆G, averaged over trials, changes over time.