Distance-wise pathway discovery from protein-protein interaction networks weighted by semantic similarity

Reconstruction of signaling pathways is crucial for understanding cellular mechanisms. A pathway is represented as a path of a signaling cascade involving a series of proteins to perform a particular function. Since a protein pair involved in signaling and response have a strong interaction, putative pathways can be detected from protein-protein interaction (PPI) networks. However, predicting directed pathways from the undirected genome-wide PPI networks has been challenging. We present a novel computational algorithm to efficiently predict signaling pathways from PPI networks given a starting protein and an ending protein. Our approach integrates topological analysis of PPI networks and semantic analysis of PPIs using Gene Ontology data. An advanced semantic similarity measure is used for weighting each interacting protein pair. Our distance-wise algorithm iteratively selects an adjacent protein from a PPI network to build a pathway based on a distance condition. On each iteration, the strength of a hypothetical path passing through a candidate edge is estimated by a local heuristic. We evaluate the performance by comparing the resultant paths to known signaling pathways on yeast. The results show that our approach has higher accuracy and efficiency than previous methods.