Ligand Similarity Complements Sequence, Physical Interaction, and Co-Expression for Gene Function Prediction

The expansion of protein-ligand annotation databases has enabled large-scale networking of proteins by ligand similarity. These ligand-based protein networks, which implicitly predict the ability of neighboring proteins to bind related ligands, may complement biologically-oriented gene networks, which are used to predict functional or disease relevance. To quantify the degree to which such ligand-based protein associations might complement functional genomic associations, including sequence similarity, physical protein-protein interactions, co-expression, and disease gene annotations, we calculated a network based on the Similarity Ensemble Approach (SEA: sea.docking.org), where protein neighbors reflect the similarity of their ligands. We also measured the similarity with functional genomic networks over a common set of 1,131 genes, and found that the networks had only small overlaps, which were significant only due to the large scale of the data. Consistent with the view that the networks contain different information, combining them substantially improved Molecular Function prediction within GO (from AUROC~0.63–0.75 for the individual data modalities to AUROC~0.8 in the aggregate). We investigated the boost in guilt-by-association gene function prediction when the networks are combined and describe underlying properties that can be further exploited.