Prediction of Binding Free Energy of Protein–Ligand Complexes with a Hybrid Molecular Mechanics/Generalized Born Surface Area and Machine Learning Method

Accurate prediction of protein–ligand binding free energies is important in enzyme engineering and drug discovery. The molecular mechanics/generalized Born surface area (MM/GBSA) approach is widely used to estimate ligand-binding affinities, but its performance heavily relies on the accuracy of its energy components. A hybrid strategy combining MM/GBSA and machine learning (ML) has been developed to predict the binding free energies of protein–ligand systems. Based on the MM/GBSA energy terms and several features associated with protein–ligand interactions, our ML-based scoring function, GXLE, shows much better performance than MM/GBSA without entropy. In particular, the good transferability of the GXLE model is highlighted by its good performance in ranking power for prediction of the binding affinity of different ligands for either the docked structures or crystal structures. The GXLE scoring function and its code are freely available and can be used to correct the binding free energies computed by MM/GBSA.