Pre‐ and post‐docking sampling of conformational changes using ClustENM and HADDOCK for protein‐protein and protein‐DNA systems

Incorporating the dynamic nature of biomolecules in the modeling of their complexes is a challenge, especially when the extent and direction of the conformational changes taking place upon binding is unknown. Estimating whether the binding of a biomolecule to its partner(s) occurs in a conformational state accessible to its unbound form (“conformational selection”) and/or the binding process induces conformational changes (“induced‐fit”) is another challenge. We propose here a method combining conformational sampling using ClustENM—an elastic network‐based modeling procedure—with docking using HADDOCK, in a framework that incorporates conformational selection and induced‐fit effects upon binding. The extent of the applied deformation is estimated from its energetical costs, inspired from mechanical tensile testing on materials. We applied our pre‐ and post‐docking sampling of conformational changes to the flexible multidomain protein‐protein docking benchmark and a subset of the protein‐DNA docking benchmark. Our ClustENM‐HADDOCK approach produced acceptable to medium quality models in 7/11 and 5/6 cases for the protein‐protein and protein‐DNA complexes, respectively. The conformational selection (sampling prior to docking) has the highest impact on the quality of the docked models for the protein‐protein complexes. The induced‐fit stage of the pipeline (post‐sampling), however, improved the quality of the final models for the protein‐DNA complexes. Compared to previously described strategies to handle conformational changes, ClustENM‐HADDOCK performs better than two‐body docking in protein‐protein cases but worse than a flexible multidomain docking approach. However, it does show a better or similar performance compared to previous protein‐DNA docking approaches, which makes it a suitable alternative.