As expected, the variance of the work distributions became smaller for longer switching lengths. Whether variance and modality are sufficient criteria to detect systems for which the unidirectional protocol will result in incorrect free energy estimates can, therefore, not be inferred from the obtained data. While unidirectional methods are typically motivated by the cost difference between the target and reference potential and the wish to avoid sampling at the target potential level of theory, this argument should be re-examined if the target potential is an NNP, which is typically slower than a classical mechanics force field, yet performant enough for these kind of applications (timing for the calculations are shown in Table ). Unlike unidirectional approaches, bidirectional methods are not susceptible to outlier work values (typically resulting from switching trajectories that are unlikely to be realized in the respective other direction). Since failures to reproduce the correct free energy estimate with unidirectional NEQ estimates are difficult to diagnose, we advise using bidirectional NEQ simulations if the computational budget allows for it.