Standard Binding Free Energy of a SIM–SUMO Complex

Interaction of the small ubiquitin-related modifier (SUMO) and peptides containing a SUMO-interacting motif (SIM) has attracted a lot of interest in recent years, yet their structural properties and relationships between the composition of the peptide and binding free energy are not completely understood. We perform molecular dynamics simulations of the complex formed by SUMO and a peptide containing the tight-binding SIM of the protein inhibitor of activated STAT. The calculated standard binding free energy of −5.06 kcal/mol is in reasonable agreement with the experimental value of −6.54 kcal/mol. Experimental results for complexes formed by SUMO and SIM dimers indicate the existence of a parallel and an antiparallel binding mode for similar SIM peptides. We find that the parallel binding mode is highly favored in the present case. Furthermore, the simulations show that residues neighboring the SIM core motif contribute strongly to the binding energy. Structurally, the complex shows differences from the picture in which the SIM core motif lies deep in the SUMO binding groove. This also supports the idea that neighboring residues play an important role in binding.