KGG: Knowledge-Guided Graph Self-Supervised Learning to Enhance Molecular Property Predictions

Molecular property prediction has become essential in accelerating advancements in drug discovery and materials science. Graph Neural Networks have recently demonstrated remarkable success in molecular representation learning; however, their broader adoption is impeded by two significant challenges: (1) data scarcity and constrained model generalization due to the expensive and timeconsuming task of acquiring labeled data, and (2) inadequate initial node and edge features that fail to incorporate comprehensive chemical domain knowledge, notably orbital information. To address these limitations, we introduce a Knowledge-Guided Graph (KGG) framework employing self-supervised learning to pre-train models using orbital-level features in order to mitigate reliance on extensive labeled datasets. In addition, we propose novel representations for atomic hybridization and bond types that explicitly consider orbital engagement. Our pre-training strategy is cost-efficient, utilizing approximately 250,000 molecules from the ZINC15 dataset, in contrast to contemporary approaches that typically require between two and ten million molecules, consequently reducing the risk of potential data contamination. Extensive evaluations on diverse downstream molecular property datasets demonstrate that our method significantly outperforms state-of-the-art baselines. Complementary analyses, including t-SNE visualizations and comparisons with traditional molecular fingerprints, further validate the effectiveness and robustness of our proposed KGG approach.