CliffRank: A Dual-Branch Framework for Activity-Cliff Ranking Prediction

Activity cliffs, structurally similar compounds with large potency differences, are widely treated as intrinsic features of chemical datasets. We argue that apart from target biology, much of our cliff understanding is a consequence of the geometry induced by the chosen molecular representation, not a property of a molecule pair itself. We designed a six-step pipeline to systematically test this hypothesis. The pipeline consists of: assessing pairwise distance geometry, cliff enrichment, activity gradient distribution, persistent homology of the cliff subspace, predictive benchmarking for a chosen pair of an embedding and a metric, and eventually, analysis of the matched molecular pairs and stereoisomers. We applied the pipeline to fifteen configurations of embeddings and metrics to build a benchmark across three distinctive datasets known of activity cliffs challenges. No representation excels on all criteria: Morgan Tanimoto provides the strongest cliff enrichment and cross-scaffold generalization; MolFormer cosine provides the only meaningful stereochemical sensitivity; MACCS and RDKit Dice fingerprints are most sensitive to matched-molecular-pair transformations; ChemBERTa fails uniformly due to embedding collapse. These findings are not a ranking. They reflect the fact that different representations encode different aspects of molecular recognition, and that choosing one implicitly defines what an activity cliff actually is.

Accurate ranking of antibody candidates according to their binding affinity is essential for therapeutic antibody discovery. However, existing methods treat affinity comparisons independently and ignore the contextual information encoded in other labeled comparisons, limiting their ability to capture antigen-specific binding landscapes. For many target antigens, a small number of experimentally characterized affinity comparisons are often available. An important question is whether the model can exploit these existing comparisons to infer antigen-specific ranking patterns that facilitate subsequent affinity ranking. This form of learning from labeled demonstrations closely resembles the paradigm of In-Context Learning, motivating us to revisit antibody affinity ranking from an ICL perspective. To this end, we propose AbICL, an ICL framework for antigen-specific antibody affinity ranking. AbICL combines a pretrained structural encoder with a context ranking head and is trained with an episodic meta-training strategy that enables the model to leverage support demonstrations for test-time adaptation without gradient updates. Experiments on the AbRank benchmark demonstrate that AbICL consistently outperforms existing ranking baselines across almost all data splits and evaluation benchmarks. Further analysis shows that the value of contextual demonstrations depends on how well they match the target inference task, and becomes increasingly pronounced under distribution shift and fine-grained affinity discrimination. These findings highlight the potential of ICL as an effective paradigm for antigen-specific antibody affinity ranking, particularly in challenging settings where a single global ranking function is insufficient.

Accurate prediction of molecular properties underpins drug discovery and material design, yet even state-of-the-art models remain vulnerable to localized failure modes that aggregate metrics cannot detect. The places where molecular similarity should be most helpful are also places where standard evaluation can be most misleading. Property cliffs expose this gap: structurally similar molecules can still differ sharply in target property, so models with competitive overall performance may fail in high-risk local neighborhoods. To expose and mitigate this failure mode, CliffSplit, a cliff-aware evaluation protocol that constructs locally supported, cliff-exposed test cases, and CliffLoss, a model-agnostic train-only mitigation mechanism for cliff-sensitive errors, are introduced. Experiments on three QM9 targets and three MoleculeNet tasks across five backbones show that CliffSplit reveals at least 15% higher error in cliff-heavy QM9 regions, while CliffLoss reduces the cliff-to-smooth error gap by up to 30% on Lipophilicity and improves overall MAE by 9.7%. Together, these results turn molecular similarity failure from a descriptive anomaly into a benchmarked evaluation problem for molecular machine learning. The code is available at https://anonymous.4open.science/r/Cliff_Loss.