Interaction-Based Inductive Bias in Graph Neural Networks: Enhancing Protein-Ligand Binding Affinity Predictions From 3D Structures

Inductive bias in machine learning (ML) is the set of assumptions describing how a model makes predictions. Different ML-based methods for protein-ligand binding affinity (PLA) prediction have different inductive biases, leading to different levels of generalization capability and interpretability. Intuitively, the inductive bias of an ML-based model for PLA prediction should fit in with biological mechanisms relevant for binding to achieve good predictions with meaningful reasons. To this end, we propose an interaction-based inductive bias to restrict neural networks to functions relevant for binding with two assumptions: 1) A protein-ligand complex can be naturally expressed as a heterogeneous graph with covalent and non-covalent interactions; 2) The predicted PLA is the sum of pairwise atom-atom affinities determined by non-covalent interactions. The interaction-based inductive bias is embodied by an explainable heterogeneous interaction graph neural network (EHIGN) for explicitly modeling pairwise atom-atom interactions to predict PLA from 3D structures. Extensive experiments demonstrate that EHIGN achieves better generalization capability than other state-of-the-art ML-based baselines in PLA prediction and structure-based virtual screening. More importantly, comprehensive analyses of distance-affinity, pose-affinity, and substructure-affinity relations suggest that the interaction-based inductive bias can guide the model to learn atomic interactions that are consistent with physical reality. As a case study to demonstrate practical usefulness, our method is tested for predicting the efficacy of Nirmatrelvir against SARS-CoV-2 variants. EHIGN successfully recognizes the changes in the efficacy of Nirmatrelvir for different SARS-CoV-2 variants with meaningful reasons.

I. Introduction

Predicting protein-ligand binding affinity (PLA) remains one of the difficult challenges for computational chemistry [1]. Rapid advancements in this domain could directly benefit drug discovery by more efficiently identifying potential drugs. While physics-based methods, such as molecular dynamics and quantum mechanics, can predict PLA with notable accuracy [2], their substantial computational demands obstruct routine use in high-throughput screening. On the other hand, molecular docking, with its manageable computational costs, has become widely utilized in large-scale structure-based virtual screening (SBVS) of compounds [3], [4], [5]. However, due to the trade-off for reduced computational requirements, the accuracy of molecular docking is inevitably compromised.