DPEA detects high-specificity domain interactions. (a) Interactions between domain families, such as the hypothetical red and blue domain families, whose members interact specifically are expected to have a low propensity, θ, because the number of interactions occurring between the domain families is a small fraction of the possible interactions (four out of 16 for two domain families of four members each). Conversely, domain interactions with a high θ will typically be between families whose members interact promiscuously. Because high-specificity domain interactions are of obvious interest to biologists, screening for domain interactions by their θ values fails to detect many important domain interactions. (b) Specific interactions of RING ubiquitin ligase domains [Pfam:PF00097, zf-C3HC4] with ubiquitin-conjugating enzymes [Pfam:PF00179, UQ_con]  in a fly protein network. The inferred domain interaction has a low θ (θ = 0.011, bottom 10%) and high E (E = 29, Table 1). This reflects the abundant evidence that the domains zf-C3HC4 and UQ_con interact, despite the low probability of interaction between any pair of these domains. (c) Specific interactions of Cyclin N-terminal domains [Pfam:PF00134, Cyclin_N] and protein kinase domains [Pfam:PF00069, Pkinase]. This interaction has a θ of 0.006, which is in the bottom 6% of θ for all domain pairs, suggesting the low propensity of interaction among members of these two domain families. However, the E score of 23 (the 13th highest score in the database) reveals the high degree of evidence for the Cyclin_N ↔ Pkinase interaction. These results show that DPEA identifies high-specificity domain interactions not detected by screening for the most probable domain interactions.