Non-interacting proteins may resemble interacting proteins: prevalence and implications

The vast majority of proteins do not form functional interactions in physiological conditions. We have considered several sets of protein pairs from S. cerevisiae with no functional interaction reported, denoted as non-interacting pairs, and compared their 3D structures to available experimental complexes. We identified some non-interacting pairs with significant structural similarity with experimental complexes, indicating that, even though they do not form functional interactions, they have compatible structures. We estimate that up to 8.7% of non-interacting protein pairs could have compatible structures. This number of interactions exceeds the number of functional interactions (around 0.2% of the total interactions) by a factor 40. Network analysis suggests that the interactions formed by non-interacting pairs with compatible structures could be particularly hazardous to the protein-protein interaction network. From a structural point of view, these interactions display no aberrant structural characteristics, and are even predicted as relatively stable and enriched in potential physical interactors, suggesting a major role of regulation to prevent them.