ICM optimization of flexible interface side-chains in protein-protein docking: successes and limitations

Juan Fernandez-Recio, University of Cambridge.
 
 

The ICM Docking and Interface Side-Chain Optimization (ICM-DISCO) was benchmarked in 24 unbound pairs for protein-protein docking [Fernandez-Recio et al. (2002) Protein Sci. 11, 280-291] and successfully evaluated in the blind CAPRI experiment (http://capri.ebi.ac.uk) [Fernandez-Recio et al. (2003) Proteins 52, 113-117]. The rigid-body docking step is able to provide thousands of candidate poses ranked by interacting energy, and gives important information about the location of the putative protein-protein interaction sites [Fernandez-Recio et al. (2004) J.Mol.Biol. 335, 843-865]. However, it is the global energy optimization of the flexible ligand interface side-chains that ultimately helps to identify the correct geometry of the complex. This flexible refinement step is especially efficient in protease-inhibitors, and generally, in cases where only a few steric clashes between the unbound side-chains need to be resolved in order to achieve the final complex structure. However, in some other cases the ligand side-chain optimization protocol is not enough to achieve the optimized fit of the interacting molecules. Both successful and not-so-successful stories will be analyzed here,and we will discuss new ways of improving flexible refinement of the interfaces in internal coordinates.