The PCSM also enables hierarchal clustering to generate a contact-based equivalent of a phylogenetic tree (i.e., a dendrogram, Figure ), using a distance measure based on how similar their interaction networks are. Analyzing the interactions that differentiate two sub-trees can yield insight into putative evolutionary or functional differences. As an example of this, we selected a branch point in the dendrogram and used this to create two groups of proteins, labelled Clusters 1 and 2 in Figure . Each contact was scored by the difference in degree of conservation between the two clusters, quantified as C2,ij -C1,ij, where C1,ij is the fraction of structures in group 1 where contact ij is present, and the resulting histogram is plotted in Figure . This histogram clearly shows most contacts do not notably differ between the two clusters. To study those contacts that differ the most between the two clusters, we selected contacts with a conservation difference of ≥±0.3. Of the 58 contacts thus selected (from 1712 total), those with the greatest difference in contact conservation are rendered in Figure , on the structure of a representative protein from each cluster. Whilst a detailed analysis of the differences in the contact networks of β-lactamases is beyond the scope of this manuscript, as an example, our comparison of Clusters 1 and 2 identified several well conserved intermolecular hydrogen bonds towards the N-terminus of the Cluster 1 βlactamases (circled on Figure ) resulting in an extended α-helix for the Cluster 1 β-lactamases. We identified the phylum to which each β-lactamase belonged in order to compare contact based hierarchal clustering against taxonomic classification (Figure ). Whilst there clearly was some level of cluster separation according to the phylum for example 9/10 of the Bacillota were clustered to the far right of the dendrogram, it could not explain all of the separations (Figure ).