Since the fourth evaluation for critical assessment of prediction of interactions (CAPRI), we have made improvements in three major areas in our refinement approach, namely the treatment of conformational flexibility, the binding free energy model, and the search algorithm. First, we incorporated backbone flexibility into our previous approach, which only optimized rigid backbone poses with limited side-chain flexibility. Here, we formulated and solved the conformational search as a hierarchical optimization problem (involving rigid-body poses, backbone flexibility, and side-chain flexibility). Second, we used continuum electrostatic calculations to include solvation effects in the binding free energy model. Finally, we eliminated sloppy modes (directions in which the free energy is essentially constant) to improve the efficiency of the search. With these improvements, we produced correct predictions for 6 of the 10 latest CAPRI targets, including one high, three medium, and two acceptable accuracy predictions. Compared to our previous performance in CAPRI, substantial improvements have been made for targets requiring homology modeling. Proteins 2013; 81:2129–2136. © 2013 Wiley Periodicals, Inc.