The Binding Domain of the HMGB1 Inhibitor Carbenoxolone: Theory and Experiment

We present a combined computational and experimental study of the interaction of the Box A of the HMGB1 protein and carbenoxolone, an inhibitor of the HMGB1 pro-inflammatory activity. The computational approach consists of classical molecular dynamics simulations using the GROMOS force field with quantum-refined parameters for the ligand. Experimental information is inferred from chemical shift displacements and X-filtered intermolecular Nuclear Overhauser Enhancement data. We find a general agreement between our experimental observations and the conformation of the ligand-protein complex resulting from our simulations. In contrast, agreement with the results obtained using simple docking procedures and with molecular dynamics based on the original force field is poor and confirms the need for the quantum refinement. The ligand-protein binding is shown to be dominated by non-bonded interactions.