Generating consistent sets of thermodynamic and structural data for analysis of protein-ligand interactions

The development of reliable, transferable methods that can compute the energy of interaction between proteins and ligands is a major challenge for computational chemistry. Understanding the energetics of protein-ligand interactions would not only provide powerful tools for prediction in structure-assisted ligand and library design, but also enrich our appreciation of the subtleties of structure that underlie molecular recognition in biological systems. One of the central problems in developing effective models is the quality and quantity of experimental data on the structure and thermodynamics of protein-ligand complexes. In this article we discuss some of the issues and some of the experimental programmes of research we have initiated to provide such data. We summarise the characteristics necessary for a model system and the experimental techniques available. This includes a discussion of calorimetry, inhibition assays and crystallographic results on series of complexes in our laboratory, including penicillin acylase, thrombin, sialidase and in particular the oligopeptide binding protein, OppA. As well as discussing the lessons we have learnt about the characteristics of an ideal model system, we also present some preliminary analyses of what our combined structural and thermodynamic data have told us.