Identifying Protein–Ligand Interactions via a Novel Distance Self-Feedback Biomolecular Interaction Network

Efficient and accurate characterizations of protein-ligand interactions are key to understanding biology at the molecular level. They are particularly useful in pharmaceutical industry applications. They are usually computationally demanding for those widely applied dynamics-based methods in identifying important residues or calculating ligand binding free energy. In this work, we proposed a graph deep learning (DL) framework, namely, the distance self-feedback biomolecular interaction network (DSBIN), in which the relationship between the complex structure and binding affinity can be established by means of a carefully designed distance self-feedback module and interaction layer. Our model can directly provide a quantitative evaluation of inhibitor binding affinities (pKd). More importantly, the DSBIN model efficiently identifies key interactions for inhibitor binding and thus intrinsically bears the interpretability. Its generalization performance was further verified using 1405 unseen structures. The predicted binding free energies' deviations were calculated to be less than 1.37 kcal/mol for more than 55% structures. Moreover, we also compared the DSBIN model with a commonly used theoretical method in calculating the substrate binding free energy, MM/GBSA. Our results show that the current DL model has generally better performance in predicting the binding free energy. For a specific complex system, mannopentaose/TmCBM27, the DSBIN predicted binding free energy is -8.21 kcal/mol, which is very close to experimentally measured -7.76 kcal/mol and MM/GBSA calculated -7.16 kcal/mol. Meanwhile, all important aromatic residues around the binding pocket can be identified by our DL model. Considering the accuracy and efficiency of the newly developed DL model, it may be very helpful in the field of drug design and molecular recognition.