ICM‐DISCO docking by global energy optimization with fully flexible side‐chains

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Abstract
The ICM‐DISCO (Docking and Interface Side‐Chain Optimization) protein–protein‐docking method is a direct stochastic global energy optimization from multiple starting positions of the ligand. The first step is performed by docking of a rigid all‐atom ligand molecule to a set of soft receptor potentials precalculated on a 0.5 Å grid from realistic solvent‐corrected force‐field energies. This step finds the correct solution as the lowest energy conformation in almost 100% of the cases in which interfaces do not change on binding. The second step is needed to deal with the induced changes and includes the global optimization of the interface side‐chains of up to 400 best solutions. The CAPRI predictions were performed fully automatically with this method. Available experimental information was included as a filtering step to favor expected docking surfaces. In three of the seven proposed targets, the ICM‐DISCO method found a good solution (>50% of correct contacts) within the five submitted models. The procedure is global and fully automated. We demonstrate that the algorithm handles the induced changes of surface side‐chains but is less successful if the backbone undergoes large‐scale rearrangements. Proteins 2003;52:113–117.