Protein – Protein interactions (PPIs) are thought to be conserved between species, although this has not been systematically investigated. This problem was explored in Escherichia coli from experimental data in Treponema pallidum by predicting PPIs, focusing on protein domains of little or unknown function. The comparison of T. pallidum to a model organism such as E. coli can not only reveal additional data about T. pallidum but also reveals how E. coli is similar to this distantly related, obligate parasite. A set of novel T. pallidum interactions, enriched for proteins of unknown function, were the basis of over 23,000 predicted homologous E. coli protein-protein and domain-domain interactions. Utilizing computational methods of protein analysis to define identity cross-species comparisons, this work shows that T. pallidum is nearly 61% similar to E. coli by orthologous groups (OG), demonstrating that what we knew of T. pallidum can be applied to E. coli. Observed binary interactions of that same pool of OGs result in only 4.3% shared T. pallidum interactions. Assigning function to proteins of unknown function leads to a greater understanding of how individual proteins relate to the larger interactome, the whole of interactions within a cell.