Critical assessment of sequence-based protein-protein interaction prediction methods that do not require homologous protein sequences

Abstract Background Protein-protein interactions underlie many important biological processes. Computational prediction methods can nicely complement experimental approaches for identifying protein-protein interactions. Recently, a unique category of sequence-based prediction methods has been put forward - unique in the sense that it does not require homologous protein sequences. This enables it to be universally applicable to all protein sequences unlike many of previous sequence-based prediction methods. If effective as claimed, these new sequence-based, universally applicable prediction methods would have far-reaching utilities in many areas of biology research. Results Upon close survey, I realized that many of these new methods were ill-tested. In addition, newer methods were often published without performance comparison with previous ones. Thus, it is not clear how good they are and whether there are significant performance differences among them. In this study, I have implemented and thoroughly tested 4 different methods on large-scale, non-redundant data sets. It reveals several important points. First, significant performance differences are noted among different methods. Second, data sets typically used for training prediction methods appear significantly biased, limiting the general applicability of prediction methods trained with them. Third, there is still ample room for further developments. In addition, my analysis illustrates the importance of complementary performance measures coupled with right-sized data sets for meaningful benchmark tests. Conclusions The current study reveals the potentials and limits of the new category of sequence-based protein-protein interaction prediction methods, which in turn provides a firm ground for future endeavours in this important area of contemporary bioinformatics.