Task-adaptive multimodal molecular representations for structure-sensitive property prediction

Abstract

Structure-sensitive properties (SSPs), including activity cliffs and chirality-dependent properties, challenge molecular machine learning because small structural perturbations can cause abrupt property changes and invalidate smooth structure–property assumptions. Here, we present CAMF (Chirality- and Activity-cliff-aware Multimodal Framework), a task-adaptive framework that models SSPs through selective integration of complementary molecular evidence. To systematically evaluate this problem, we construct SSPBench, a benchmark spanning 77 conventional ADMET and physicochemical tasks together with activity-cliff and chirality-sensitive benchmarks. CAMF integrates molecular embeddings and expert-defined descriptors using random-forest-based feature selection and adaptive fusion, enabling property-specific prioritization of informative signals while reducing multimodal redundancy. Across ten baselines, CAMF achieves the best overall performance on SSP tasks, improving mean R2 by up to 29.5% on activity-cliff datasets and reducing MAE by up to 23.3% on 90 364 chiral molecules with TD-DFT-computed optical rotatory strengths. Ablation analyses show that these gains arise from task-adaptive multimodal integration rather than naive feature concatenation. More broadly, our results reveal that modality relevance is strongly task-dependent, with descriptors and 3D geometry becoming especially important in non-smooth property regimes. Case studies further support the interpretability and practical utility of CAMF in identifying activity-associated substructures and clinically relevant toxicity liabilities.