AbstractThe ICM Docking and Interface Side‐Chain Optimization (ICM‐DISCO) showed promising predictive results during the first CAPRI experiment by successfully finding medium‐ or high‐accuracy models in 3 of the 7 targets. A key factor was the ability to recognize near‐native rigid‐body geometries in a relatively low number of alternative docking poses, together with the successful refinement of the rigid‐body docking interfaces. Since then, we have focused on improving the scoring function to optimally discriminate the near‐native rigid‐body conformations. For that, we have defined a new desolvation descriptor for rigid‐body docking, based on atomic solvation parameters (ASPs) derived from octanol–water transfer experiments. This and other new approaches have been gradually incorporated into our docking procedure during our participation on the second CAPRI experiment. Overall, we produced reasonable models for 8 of the 9 official targets. Especially encouraging were those cases in which a homology model of 1 of the subunits had to be used during the docking simulations. And not less gratifying has been the successful prediction of antibody–antigen targets in a completely automatic, unrestrained fashion. In summary, our success rate (89%) shows a consistent improvement over the previous CAPRI rounds, and suggests that a correct desolvation description is key for improved protein–protein docking predictions. Proteins 2005;60:308–313. © 2005 Wiley‐Liss, Inc.