This can be seen, e.g., for the hp7 system, where the unidirectional estimation of ∆G MM→NNP is more susceptible to the impact of the bimodal work distribution than the unidirectional estimation of ∆G NNP→MM (note that we plot p(-w NNP→MM ) in Figure ). The origin of the bi-modality of the work distributions for hp7 is analyzed in detail below. The most extreme case is hp19; here high variance and bi-modality/skewness dominate the work distributions.