Protein interaction databases are critical resources for network bioinformatics and integrating molecular experimental data. Interaction databases may also enable construction of predictive computational models of biological networks, although their fidelity for this purpose is not clear. Here, we benchmark protein interaction databases X2K, Reactome, Pathway Commons, and Signor for their ability to recover manually curated edges from three logic-based network models of cardiac hypertrophy, mechano-signaling, and fibrosis. Pathway Commons performed best at recovering interactions from manually reconstructed hypertrophy (137 of 193 interactions, 71%), mechano-signaling (85 of 125 interactions, 68%), and fibroblast networks (98 of 142 interactions, 69%). While protein interaction databases successfully recovered central, well-conserved pathways, they performed worse at recovering tissue-specific and transcriptional regulation. This highlights a knowledge gap where manual curation is critical. Finally, we tested the ability of Signor and Pathway Commons to identify new edges that improve model predictions, revealing important roles of PKC autophosphorylation and CaMKII phosphorylation of CREB in cardiomyocyte hypertrophy. This study provides a platform for benchmarking protein interaction databases for their utility in network model construction, as well as providing new insights into cardiac hypertrophy signaling.

Protein interaction databases are critical resources for network bioinformatics and integrating molecular experimental data. Interaction databases may also enable construction of predictive computational models of biological networks, although their fidelity for this purpose is not clear. Here, we benchmark protein interaction databases X2K, Reactome, Pathway Commons, Omnipath and Signor for their ability to recover manually curated edges from three logic‐based network models of cardiac hypertrophy, mechano‐signalling and fibrosis. Pathway Commons performed best at recovering interactions from manually reconstructed hypertrophy (137 of 193 interactions, 71%), mechano‐signalling (85 of 125 interactions, 68%) and fibroblast networks (98 of 142 interactions, 69%). While protein interaction databases successfully recovered central, well‐conserved pathways, they performed worse at recovering tissue‐specific and transcriptional regulation. This highlights a knowledge gap where manual curation is critical. Finally, we tested the ability of Signor and Pathway Commons to identify new edges that improve model predictions, revealing important roles of protein kinase C autophosphorylation and Ca2+/calmodulin‐dependent protein kinase II phosphorylation of CREB in cardiomyocyte hypertrophy. This study provides a platform for benchmarking protein interaction databases for their utility in network model construction, as well as providing new insights into cardiac hypertrophy signalling. imageKey points Protein interaction databases are used to recover signalling interactions from previously developed network models. The five protein interaction databases benchmarked recovered well‐conserved pathways, but did poorly at recovering tissue‐specific pathways and transcriptional regulation, indicating the importance of manual curation. We identify new signalling interactions not previously used in the network models, including a role for Ca2+/calmodulin‐dependent protein kinase II phosphorylation of CREB in cardiomyocyte hypertrophy.