### Half-Space Proximal Networks (HSPNs) Facilitate the Extraction of Representative CnSA Datasets  
The chemical space of the CnSAs is superimposed over the chemical spaces of the DRAMP and StarPepDB databases by projecting a composite HSPN, made up of the three datasets (Figure 5). This analysis suggests that CnSAs occupy a different chemical space, concentrated in the red zone. These CnSAs have five distinct clusters, suggesting they may have distinct physicochemical properties and actions against microbial cells (Figure 6a). Cluster 4 contains the highest number of peptides (30.35%), followed by Cluster 2 (19.97%), Cluster 0 (19.62%), Cluster 3 (17.25%), and Cluster 1 (12.81%) (Figure 6b). To detect the most representative CnSA from the HSPN, we applied the harmonic (HC) and hub-bridge (HB) centrality measures. These measures of centrality are very popular in network science for the detection of relevance along all networks and within their clusters, respectively. This analysis resulted in the extraction of 1505  
Figure 4: Heatmaps of the pairwise sequence identity of the 3121 and 1411 non-haemolytic and non-toxic AMPs were obtained after comparison with the publicly available AMP databases DRAMP and StarPepDB, respectively, with a sequence identity cutoff of 0.40 using CD-HIT-2D. The union of both datasets was selected, which represents the 3130 Cnidaria Singular AMPs (CnSAs). The heatmap and histogram of the pairwise sequence identity of the CnSAs were constructed, demonstrating similarities generally below 30%.  
and 1447 representative AMPs from the 3310 CnSAs, respectively. The union and intersection of the two centrality-based subsets generated 1935 and 1017 unique AMPs, respectively (Figure 6c). Again, the chemical space of the intersection subset of the most representative CnSA is superimposed over the chemical spaces of the DRAMP and StarPepDB databases, confirming its representativeness when centralized over the CnSAs (Figure 5).  
The characterization of the CnSAs within the HSPN is provided in Supplementary File S5, detailing properties for each of the 3310 nodes and the HC and HB values. An HSPN was also constructed to represent the chemical space of the intersection dataset (1017) of the most representative CnSA, retaining the same five clusters of the previously mentioned space, depicted in Figure 6a However, their peptide content varies. Cluster 4 contains the highest number of peptides (23.21%), followed by Cluster 2 (22.42%), Cluster 3 (20.55%), Cluster 0 (19.37%), and Cluster 1 (14.45%) (Supplementary Figure S5). The FASTA files corresponding to the CnSA extracted via harmonic and hub-bridge network centralities, as well as for the union and intersection datasets, are available in Dataset 9. We considered the union dataset (1955) as the representative and comprehensive AMP dataset for further analysis. Cluster 4 has the highest percentage of representative AMPs (27.18%), followed by Cluster 0 (21.91%), Cluster 2 (21.14%), Cluster 3 (18.14%), and Cluster 1 (11.63%) (Figure 7a). The mean values for each characteristic are represented in Figure 7b.  
Figure 5: Workflow of the chemical space analysis using Half-Space Proximal Networks (HSPN) to uncover Cnidaria Singular AMPs (CnSAs). **I**: Visualization of the chemical spaces of DRAMP (yellow; 4951 AMPs) and StarPepDB (blue; 19,456 AMPs) databases. **II**: Superimposition of the CnSAs (light red; 3130 AMPs) on the chemical spaces of DRAMP and StarPepDB databases, separately; **III**: Representation of the HSPN of the extracted 3130 CnSA, demonstrating the presence of five distinct clusters. **IV**: Superimposition of the representative CnSA (dark red; 1107 AMPs) on the chemical spaces of DRAMP and StarPepDB databases, separately, which is centralized over the CnSA.