Global protein function prediction from protein-protein interaction networks

Determining protein function is one of the most challenging problems of the post-genomic era. The availability of entire genome sequences and of high-throughput capabilities to determine gene coexpression patterns has shifted the research focus from the study of single proteins or small complexes to that of the entire proteome(1). In this context, the search for reliable methods for assigning protein function is of primary importance. There are various approaches available for deducing the function of proteins of unknown function using information derived from sequence similarity or clustering patterns of coregulated genes(2,3), phylogenetic profiles(4), protein-protein interactions (refs. 5-8 and Samanta, M. P. and Liang, S., unpublished data), and protein complexes(9,10). Here we propose the assignment of proteins to functional classes on the basis of their network of physical interactions as determined by minimizing the number of protein interactions among different functional categories. Function assignment is proteome-wide and is determined by the global connectivity pattern of the protein network. The approach results in multiple functional assignments, a consequence of the existence of multiple equivalent solutions. We apply the method to analyze the yeast Saccharomyces cerevisiae protein-protein interaction network(5). The robustness of the approach is tested in a system containing a high percentage of unclassified proteins and also in cases of deletion and insertion of specific protein interactions.