Estimating Absolute Protein–Protein Binding Free Energies by a Super Learner Model

Protein-protein binding is central to most biochemical processes of all living beings. Its importance underlies mechanisms ranging from cell interactions to metabolic control, but also to <i>ex vivo</i> biotechnology, such as the development of therapeutic monoclonal antibodies, the engineering of enzymes for industrial biocatalysis, the development of biosensors for disease detection, and the assembly of artificial protein complexes for drug screening. Therefore, predicting the strength of their association allows for understanding the molecular mechanisms and ultimately controlling them. We devised a machine learning ensemble model that uses Rosetta-based quantities to predict binding free energies of protein-protein complexes with accuracy rivaling both computationally demanding methods and currently available ML/DL tools. The method was encoded into an application Python pipeline named PBEE, which stands for Protein Binding Energy Estimator, allowing a rapid calculation of the absolute binding free energies of protein complexes from their PDB coordinates.