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 its pro-inflammatory activity. The computational approach consists of classical molecular dynamics (MD) simulations based on the GROMOS force field with quantum-refined (QRFF) atomic charges for the ligand. Experimental data consist of fluorescence intensities, chemical shift displacements, saturation transfer differences and intermolecular Nuclear Overhauser Enhancement signals. Good agreement is found between observations and the conformation of the ligand-protein complex resulting from QRFF-MD. In contrast, simple docking procedures and MD based on the unrefined force field provide models inconsistent with experiment. The ligand-protein binding is dominated by non-directional interactions.