The proponents of the NEQ method claim that a major advantage of this method over the EQ method is that it is computationally cheaper as well as requiring less wall clock time to run. However, both these claims are unjustified on systematically comparing both methods and implementing them in a reliable and consistent way. In Table and the related section, we have established that the computational costs associated with the NEQ method is only about 10% lower than that of the EQ method using the standard protocol, which is already much less of a saving than often claimed in the literature. Further, the majority of this difference in the overall computational cost is accountable to the thermodynamic leg involving ligand in the water environment. In fact, the simulation time involving protein is 100 ns less in case of the EQ approach (1500 ns vs 1600 ns; see Table ) which more than compensates for the higher simulation time required for the ligand-only calculations, effectively nullifying the difference in computational costs of the two approaches. Moreover, our results show that, using the recommended protocols, the number of systems with insufficiently accurate and/or precise results are significantly higher in case of the NEQ approach in comparison to the EQ approach; about half the complexes do not meet both the criteria of reliability as already described above. On top of that, NEQ calculations need to satisfy the additional criterion of non-zero overlap which makes it more stringent. Therefore, the additional simulation time required to be invested in order to get reliable predictions is far higher in case of NEQ, more than wiping out the apparent fractional cost savings. Thus, the real savings in terms of computational costs are negligible at best, if not negative. To make things worse, one cannot reuse the previously run NEQ transitions which need to be rerun from scratch, adding to the computational costs substantially. For instance, simply increasing the transition length alone from 400 ps to 800 ps adds an extra computation of 800 ns per ∆G com component (using the recommended "standard" protocol) since the previous transitions of 400 ps are useless. It should be noted that all the above arguments are equally valid in the case of RBFE calculations using the NEQ approach, due to which the EQ approach is preferable in that case too .