Instantaneous or non-equilibrium methods can be used to estimate free energy differences between levels of theory Indirect free energy calculations can be performed using a variety of methods. Since the target is typically a more expensive Hamiltonian, the focus has been on methods that avoid sampling with the target Hamiltonian: single-step free-energy perturbation (FEP) or unidirectional non-equilibrium (NEQ) switching simulations. In FEP, the potential energy difference between reference and target potential, ∆U (x) = β(U NNP (x) -U MM (x)) is related to the equilibrium free energy difference using the Zwanzig relationship. However, this method can be impractical due to the typically high variance (σ 2 ) of the potential energy difference values (σ 2 ≫ (k B T ) 2 ) because of changes in the potential energy landscape between the potentials. This may result in a systematic bias of the free energy estimate caused by the sensitivity of the non-linear exponential average (EXP) estimator to values at the left tail of the potential energy difference distribution (a region that is, per definition, not well sampled). If the variance of the ∆U (x) distribution is significant, obtaining converged free energy estimates can become prohibitively expensive.