One way to reduce the variance of the work values and improve the effective sample size sufficiently is the use of non-equilibrium simulations, which involve slowly perturbing the system from the reference to the target potential while using a series of local moves, such as Monte Carlo or MD simulations. The Jarzynski equation recovers the equilibrium free energy estimate from the work accumulated during the NEQ process. NEQ simulations are an elegant and efficient method for performing indirect free energy calculations, especially for systems with significant changes in the potential energy landscape. Note that the two methods are related: for instantaneous NEQ switching, the initial and final point of the switching trajectory are identical, as the system has no time to evolve, and the NEQ switching simulation reduces to the FEP formalism. Unidirectional FEP and NEQ switching simulations are prone to the same failure scenario, even though FEP is to a much greater extent. Slow degrees of freedom make sampling from the equilibrium Boltzmann distribution challenging, significantly increasing the time needed for any given estimator to converge to the correct free energy estimate. For correct, converged FEP calculations, a sufficient number of configurations sampled at the low level of theory needs to be relevant at the high level. In the case of NEQ switching, a sufficient number of switches must follow trajectories representing the reverse directions (high to low). If sampling with the target and reference Hamiltonian is feasible, FEP and NEQ switching simulations can be performed bidirectionally by calculating the forward (low to high) and reverse work/∆U . By using both forward and reverse work or ∆U values, one can compute accurate and asymptotically unbiased free energy estimates based on the Crooks relation using the Bennett's acceptance ratio (BAR) estimator. The speed of NNPs allows the use of equilibrium free energy calculations A challenge for indirect FES is to obtain rigorous reference values to validate the particular approach used. Analogous to Goette and Grubmüller and Giese and York 26 , we compare the FEP and NEQ protocols to multistate equilibrium free energy simulations (MFES). MFES generate a ladder of overlapping equilibrium Boltzmann distributions connecting a reference Hamiltonian (MM) with the target Hamiltonian (NNP). The free energy can be calculated using the Multistate Bennett's acceptance ratio (MBAR) estimator. While MFES protocols are prohibitively expensive using semi-empirical or ab initio QM as the target level of theory, using fast NNPs makes such free energy simulations feasible.