To validate this through the idea of Similar Property Principle (SPP), we calculated the Jaccard distance for each tautomer pair using Morgan fingerprints (radius 2 and 3) and plotted it against the absolute Gibbs free energy difference (Fig. ). Overall, the results show that as the similarity between tautomer pairs increases (localized tautomerization), the Gibbs free energy difference decreases. However, the correlation is non-linear, suggesting the multivariate complexity resulting from structural changes and environmental factors (such as solvent effects) that contribute to the non-linearity, particularly at lower similarities (less than We then turned to determining the statistical significance of these energetic differences through paired means or medians testing. Even though outliers are present in the distributions (30 for centroids and 20 for rigids, based on Tukey's Fence method with outside rate of k = 2.2), we do not consider them as typical outliers that need to be excluded. Because our analysis seeks to understand energetic consequences of both ChemAxon and RDKit tautomer canonicalization, we retained these "outliers" for a more complete comparison. Therefore, it is important to focus on statistical tests that are robust to both the underlying distribution and presence of outliers (see Statistical analysis section of Computational Methods). Results for these statistical tests are summarized in Table . Results for non-parametric tests.