Comparing the obtained ∆∆G values from the different approaches revealed no significant differences between them. Interestingly, in the case of TYK2, the average statistics seemed to worsen with the MST layout compared to the radial layout, although this change was not statistically significant (see Table , SI-Table , SI-Figure , and SI-Table ). None of the approaches yielded any outliers exceeding 2 kcal/mol deviation from the experimental values (see SI-Figure and SI-Figure ).