InteractionNet: Modeling and Explaining of Noncovalent Protein-Ligand Interactions with Noncovalent Graph Neural Network and Layer-Wise Relevance Propagation

Expanding the scope of graph-based, deep-learning models to noncovalent protein-ligand interactions has earned increasing attention in structure-based drug design. Modeling the protein-ligand interactions with graph neural networks (GNNs) has experienced difficulties in the conversion of protein-ligand complex structures into the graph representation and left questions regarding whether the trained models properly learn the appropriate noncovalent interactions. Here, we proposed a GNN architecture, denoted as InteractionNet, which learns two separated molecular graphs, being covalent and noncovalent, through distinct convolution layers. We also analyzed the InteractionNet model with an explainability technique, i.e., layer-wise relevance propagation, for examination of the chemical relevance of the model's predictions. Separation of the covalent and noncovalent convolutional steps made it possible to evaluate the contribution of each step independently and analyze the graph-building strategy for noncovalent interactions. We applied InteractionNet to the prediction of protein-ligand binding affinity and showed that our model successfully predicted the noncovalent interactions in both performance and relevance in chemical interpretation.