This voting system identified the transformation from compound 03 to compound 01 (Figure ) as the worst edge and indeed, fol-low up work showed that this transformation suffered from significant sampling problems. For this transformation the standard deviation across three independent repeats was low (0.2 kcal/mol). However, running the transformation in the opposite direction (compound 01 → compound 03) gave very different results (∆∆G = 1.1 ± 0.1 kcal/mol) than the original direction (∆∆G = 0.8 ± 0.2 kcal/mol, before accounting for the sign flip). This difference of 1.9 kcal/mol depending on the direction indicated sampling problems in this edge.