Learning Protein-Ligand Binding in Hyperbolic Space
1. HypSeek, a new hyperbolic representation learning framework, improves virtual screening and affinity ranking for drug discovery by embedding ligands, protein pockets, and sequences into Lorentz-model hyperbolic space. It leverages the space's exponential geometry and negative curvature to better model molecular interactions.
2. The model shows significant improvements on benchmarks, increasing early enrichment in virtual screening on DUD-E from 42.63% to 51.44% and affinity ranking correlation on JACS from 0.5774 to 0.7239.
3. A key strength of HypSeek is its ability to handle "activity cliffs," cases where structurally similar ligands have very different binding affinities. The hyperbolic space can amplify functional differences even when structural similarities are tight, a task where Euclidean embeddings struggle.
4. The theoretical analysis confirms that hyperbolic geometry is better for separating these challenging ligand pairs. Euclidean distance grows linearly, while hyperbolic distance grows exponentially, allowing for greater separation of functionally different but structurally similar molecules.
5. The framework unifies both virtual screening and affinity ranking tasks and introduces a protein-guided three-tower architecture to enhance representational structure.
6. A comparison with the state-of-the-art LigUnity model on activity cliff pairs shows that HypSeek's hyperbolic score differences are an order of magnitude larger than Euclidean score differences, providing a clearer distinction between ligands.
7. Even in cases where free energy perturbation (FEP) predicts the wrong direction of affinity change, the hyperbolic score still aligns with the experimental ordering.
8. The paper provides a detailed theoretical motivation for why hyperbolic space is better suited for this problem, demonstrating how small angular differences in the hyperbolic embedding can lead to large separations.
9. The authors also outline the metrics used for virtual screening and affinity ranking, including AUROC, BEDROC80.5, Enrichment Factor, and Pearson and Spearman correlations.
10. This work highlights the potential of hyperbolic geometry as a powerful inductive bias for protein-ligand modeling, offering a more expressive and affinity-sensitive approach.
📜Paper:
arxiv.org/abs/2508.15480
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