Learning Molecular Semantic Invariant Representation with Prototype Constraint

摘要

Molecular representation learning has achieved remarkable progress in molecular property prediction, yet out-of-distribution (OOD) generalization remains challenging. In practice, training data typically cover only a limited portion of the chemical space, causing models to rely on environment-dependent factors that fail to transfer when scaffold structures or functional compositions shift. To address this issue, we propose MoSIR, a framework for learning molecular semantic invariant representation with prototype constraint, which projects entangled molecular embeddings into a learnable semantic prototype space to extract semantic invariant representation while isolating environment-sensitive variations. Building upon this decomposition, we optimize a bi-level min-max objective that introduces representation perturbations to simulate plausible environment shifts and enforce semantic stability. We further provide theoretical guarantees for MoSIR by deriving an OOD generalization bound under distribution shifts. Extensive experiments on multiple molecular OOD benchmarks demonstrate that MoSIR consistently outperforms strong baselines across diverse shift settings, and qualitative analyses confirm that the learned prototypes capture meaningful chemical semantics.