LINKER: Learning Interactions Between Functional Groups and Residues With Chemical Knowledge-Enhanced Reasoning and Explainability

Abstract

Accurate identification of interactions between protein residues and ligand functional groups is essential to understand molecular recognition and guide rational drug design. Existing deep learning approaches for protein-ligand interpretability often rely on 3D structural input or use distance-based contact labels, limiting both their applicability and biological relevance. We introduce LINKER, the first sequence-based model to predict residue-functional group interactions in terms of biologically defined interaction types, using only protein sequences and the ligand SMILES as input. LINKER is trained with structure-supervised attention, where interaction labels are derived from 3D protein-ligand complexes via functional group-based motif extraction. By abstracting ligand structures into functional groups, the model focuses on chemically meaningful substructures while predicting interaction types rather than mere spatial proximity. Crucially, LINKER requires only sequence-level input at inference time, enabling large-scale application in settings where structural data is unavailable. Experiments on the LP-PDBBind benchmark demonstrate that structure-informed supervision over functional group abstractions yields interaction predictions closely aligned with ground-truth biochemical annotations.