  Calculating free energy differences is a topic of substantial interest and
has many applications including molecular docking and hydration, solvation, and
binding free energies which is used in computational drug discovery. However,
in equilibrium methods the compared molecules are required to have large phase
space overlap, which is usually not satisfied for two random systems, and there
remain the challenges of robustness and automation. Here a highly efficient and
robust method, that enables a wide range of comparisons, will be introduced,
demonstrated and compared. In this method instead of transforming between one
system into the other to perform the calculation each system is transformed
into its replica with the different long range energy terms relaxed, which is
inherently correlated with the original one, in order to eliminate the
partition function difference arising from these terms. Then, since each
transformed system can be treated as non interacting systems, the remaining
difference in the (originally highly complex) partition function will cancel
out.
