LINKER: Learning Interactions between Functional Groups and Residues with Chemical Knowledge-Enhanced Reasoning and...

Accurate identification of interactions between protein residues and ligand functional groups is critical for understanding molecular recognition and guiding rational drug design. Existing deep learning approaches for protein-ligand interpretability typically rely on three-dimensional structural input or distance-based contact labels, which limit both their applicability and biological relevance. Here, we present LINKER, the first sequence-based model to predict residue-functional group interactions according to biologically defined interaction types, using only a protein sequence and the SMILES representation of the ligand. LINKER is trained via structure-supervised interaction learning, in which interaction labels are derived from three-dimensional protein-ligand complexes through functional group-based motif extraction. By representing ligands as ensembles of functional groups, the model emphasizes chemically meaningful substructures rather than mere spatial proximity. Importantly, LINKER requires only sequence-level input at inference, enabling large-scale applications in contexts where structural data are unavailable. Extensive experiments demonstrate that LINKER consistently outperforms established baselines, highlighting the utility of functional group abstractions and structure-based supervision for interpretable protein-ligand interaction prediction. Our source code is publicly available at: https://github.com/HySonLab/LINKER/.