Explainable molecular property prediction : aligning chemical concepts with predictions via language models

Abstract

Providing explainable molecular property predictions is critical for many scientific domains, such as drug discovery and material science. Though transformer-based language models have shown great potential in accurate molecular property prediction, they neither provide chemically meaningful explanations nor faithfully reveal the molecular structure-property relationships. In this work, we develop a framework for explainable molecular property prediction based on language models, dubbed as Lamole, which can provide chemical concepts-aligned explanations. We take a string-based molecular representation — Group SELFIES — as input tokens to pre-train and fine-tune our Lamole, as it provides chemically meaningful semantics. By disentangling the information flows of Lamole, we propose considering both self-attention weights and gradients for better quantification of each chemically meaningful substructure’s impact on the model’s output. To make the explanations more faithful to the structureproperty relationship, we then carefully craft a marginal loss to explicitly optimize the explanations to align with the chemists’ annotations. We bridge the manifold hypothesis with the elaborated marginal loss to prove that the loss can align the explanations with the tangent space of the data manifold, leading to concept-aligned explanations. Experimental results over eight datasets demonstrate Lamole can achieve comparable prediction accuracy and boost the explanation accuracy by up to 14.3%, being the state-of-the-art in explainable molecular property prediction. To further illustrate the actionable utility of the explanations derived from Lamole, we integrated the framework with an evolutionary algorithm. This integration established an interpretable optimization pipeline for molecular editing, demonstrating that Lamole functions beyond simple post-hoc analysis but serves as a practical guide for molecule discovery.