Refinement of protein‐protein complexes in contact map space with metadynamics simulations

Accurate protein‐protein complex prediction, to atomic detail, is a challenging problem. For flexible docking cases, current state‐of‐the‐art docking methods are limited in their ability to exhaustively search the high dimensionality of the problem space. In this study, to obtain more accurate models, an investigation into the local optimization of initial docked solutions is presented with respect to a reference crystal structure. We show how physics‐based refinement of protein‐protein complexes in contact map space (CMS), within a metadynamics protocol, can be performed. The method uses 5 times replicated 10 ns simulations for sampling and ranks the generated conformational snapshots with ZRANK to identify an ensemble of n snapshots for final model building. Furthermore, we investigated whether the reconstructed free energy surface (FES), or a combination of both FES and ZRANK, referred to as CS(α), can help to reduce snapshot ranking error.