Our findings, summarized in Figure , indicate that FEP is poorly suited to accurately estimate the free energy difference between the two levels of theory. The variance of the ∆U distributions is typically high, and obtaining configurations that have a finite probability of appearing in both the MM→NNP and NNP→MM ∆U distributions requires longer simulations than were performed in this work. While most bidirectional FEP results were accurate, the lack of overlap between the ∆U distributions should caution against using FEP for this kind of calculation (see Figures ).