Incorporating Water Molecules into Highly Accurate Binding Affinity Prediction for Proteins and Ligands.

In the binding process between proteins and ligand molecules, water molecules play a pivotal role by forming hydrogen bonds that enable proteins and ligand molecules to bind more strongly. However, current methodologies for predicting binding affinity overlook the importance of water molecules. Therefore, we developed a model called GraphWater-Net, specifically designed for predicting protein-ligand binding affinity, by incorporating water molecules. GraphWater-Net employs topological structures to represent protein atoms, ligand atoms and water molecules, and their interactions. Leveraging the Graphormer network, the model extracts interaction features between nodes within the topology, alongside the interaction features of edges and nodes. Subsequently, it generates embeddings with attention weights, inputs them into a Softmax function for regression prediction, and ultimately outputs the predicted binding affinity value. Experimental results on the Comparative Assessment of Scoring Functions (CASF) 2016 test set show that the introduction of water molecules into the complex significantly improves the prediction performance of the proposed model for protein and ligand binding affinity. Specifically, the Pearson correlation coefficient () exceeds that of current state-of-the-art methods by a margin of 0.022 to 0.129. By integrating water molecules, GraphWater-Net has the potential to facilitate the rational design of protein-ligand interactions and aid in drug discovery.