Genome and network visualization facilitates the analyses of the effects of drugs and mutations on protein-protein and drug-protein networks

Abstract

Background: Biologists generally interrogate genomics data using web-based genome browsers that have limited analytical potential. New generation genome browsers such as the Integrated Genome Browser (IGB) have largely overcome this limitation and permit customized analyses to be implemented using plugins. We illustrate the use of a plugin for IGB that exploits advanced visualization techniques to integrate the analysis of genomics data with network and structural approaches. Results: We show how visualization technologies that combine both genomics and network biology can facilitate the selection of the key amino acid contacts from protein-protein and protein-drug interactions. Starting from the MDM2-P53 interaction, which is a high-value target for cancer therapy, and Nutlin, the parent small molecule of an MDM2 antagonist that is currently in clinical trials, we show that this method can be generalized to analyze how drugs and mutations can interfere with both protein-protein and drug-protein networks. We illustrate this point by two additional use-cases exploring the molecular basis of tamoxifen side effects and of drug resistance in chronic myeloid leukemia patients. Conclusions: Combined network and structure biology approaches provide key insights into both the genetic and the edgetic roles of variants in diseases. 3D interactomes facilitate the identification of disease-relevant interactions that can then be specifically targeted by drugs. Recent advances in molecular interaction and structure visualization tools have greatly simplified the mapping of mutated residues to molecular interaction interfaces. Such approaches can now also be integrated with genome visualization tools to enable comparative analyses of interaction contacts.