Efficient refinement and free energy scoring of predicted protein- Protein complexes using replica exchange with repulsive scaling

Accurate prediction and evaluation of protein-protein complex structures are of major importance to understand the cellular interactome. Typically, putative complexes are predicted based on docking methods, and simple force field or knowledge-based scoring functions are applied to evaluate single complex structures. We have extended a replica-exchange-based scheme employing different levels of a repulsive biasing between partners in each replica simulation (RS-REMD) to simultaneously refine and score protein-protein complexes. The bias acts specifically on the intermolecular interactions based on an increase in effective pairwise van der Waals radii (repulsive scaling (RS)-REMD) without affecting interactions within each protein or with the solvent. The method provides a free energy score that correlates quite well with experimental binding free energies on a set of 36 complexes with correlation coefficients of 0.77 and 0.55 in explicit and implicit solvent simulations, respectively. For a large set of docked decoy complexes, significant improvement of docked complexes was found in many cases with the starting structure in the vicinity (within 20 Å) of the native complex. In the majority of cases (14 out of 20 in explicit solvent), near native docking solutions were identified as the best scoring complexes. The approach is computational demanding but may offer a route for refinement and realistic ranking of predicted protein-protein docking geometries.