PRISM: Prior Relational Information for Self-supervised Modeling to Enhance Solubility OOD Generalization

Xinyi Chen, Jiahuan Pang, Titus Chima, Paul Weng, Wendong Wang

Solubility depends on intermolecular interactions between solutes and solvents, and is central to drug discovery, chemical and materials process engineering. Its prediction requires out-of-distribution (OOD) generalization to unseen solutes, solvents, and solvent mixtures, where supervised methods suffer from data scarcity, and existing self-supervised methods do not explicitly learn chemically meaningful relations. Learning chemically meaningful relational information without labels can alleviate data scarcity and improve OOD generalization, but remains challenging. We introduce Prior Relational Information for Self-supervised Modeling (PRISM) and apply it to solubility OOD generalization. PRISM is a label-free pretraining framework that converts expert-defined chemical priors into relational teachers. For solubility prediction, it trains four encoders to preserve the population-level relational information from priors capturing hydrophobic, electrostatic, polarizability, and substructural effects, using Kullback-Leibler (KL) divergence to match distance-based neighborhood distributions during pretraining. Across scaffold, solute, and solvent OOD settings, PRISM matches or…