The prediction of protein complexes from high-throughput protein-protein interaction (PPI) data remains an important challenge in bioinformatics. Three groups of complexes have been identified as problematic to discover. First, many complexes are sparsely connected in the PPI network, and do not form dense clusters that can be derived by clustering algorithms. Second, many complexes are embedded within highly-connected regions of the PPI network, which makes it difficult to accurately delimit their boundaries. Third, many complexes are small (composed of two or three distinct proteins), so that traditional topological markers such as density are ineffective.
Yong, C. H., & Wong, L. (2015). Prediction of problematic complexes from PPI networks: Sparse, embedded, and small complexes. Biology Direct, 10(1). https://doi.org/10.1186/s13062-015-0067-4