Specifics of Metabolite-Protein Interactions and Their Computational Analysis and Prediction

Computational approaches to the characterization and prediction of compound-protein interactions have a long research history and are well established, driven primarily by the needs of drug development. While, in principle, many of the computational methods developed in the context of drug development can also be applied directly to the investigation of metabolite-protein interactions, the interactions of metabolites with proteins (enzymes) are characterized by a number of particularities that result from their natural evolutionary origin and their biological and biochemical roles, as well as from a different problem setting when investigating them. In this review, these special aspects will be highlighted and recent research on them and developed computational approaches presented, along with available resources. They concern, among others, binding promiscuity, allostery, the role of posttranslational modifications, molecular steering and crowding effects, and metabolic conversion rate predictions. Recent breakthroughs in the field of protein structure prediction and newly developed machine learning techniques are being discussed as a tremendous opportunity for developing a more detailed molecular understanding of metabolism.