Lomap with the experimental data, we observed no significant differences in terms of root mean square error (RMSE), mean unsigned error (MUE), Pearson correlation coefficient (ρ P ears ), and Kendall's tau (τ Kendal ) between the different approaches (see Table ). However, two clear outliers were observed in the ∆∆G correlation plots (see SI-Figure and SI-Table ). These outliers correspond to the ligand transformations 12 -8 and 12 -5, which consistently showed high deviations from the experimental values in all approaches. These deviations could potentially be attributed to sampling issues in the hybrid topology approach, particularly for the complex transformations involving ligand 5, which was already identified as difficult in the previous work. Similarly, for the transformation 12 -8, the presence of a flexible and long aliphatic chain in ligand 8 may be causing sampling difficulties.