Nevertheless, these observations were not significant. Based on the analysis of the HIF2A dataset, we can conclude that all three approaches (Kartograf, 2D Lomap, and 3D Lomap) demonstrate a comparable performance. Despite the complexity of the dataset, none of the approaches showed a significant advantage over the others in terms of ∆∆G performance (See SI-Figure and SI-Table ). 0.26 ± 0.11 0.22 ± 0.12 0.18 ± 0.12 0.29 ± 0.12 0.18 ± 0.14 0.22 ± 0.14 To investigate the impact of 're-alignments' by the Lomap mapping approaches, that inverted the coordinates of a benzyl substituent potentially impacting the binding mode during simulations, a torsion analysis was conducted for molecule ligand 163. The analysis focused on the torsional distributions of all heavy atom-related dihedrals in both water and complex simulations.