Hierarchical Molecular Representation Learning via Fragment-Based Self-Supervised Embedding Prediction

Self-supervised pretraining on molecular graphs has emerged as a promising approach for molecular property prediction, yet most existing methods operate at a single structural granularity and treat bond information as auxiliary edge attributes rather than as an independent semantic layer. In this work, we propose MolCHG, a multi-level self-supervised pretraining framework built upon a novel Compositional Hierarchical Graph that organizes molecular structure into four types of nodes across three semantic levels. By introducing a bond graph that operates in parallel with the atom graph, our architecture elevates bond-level information to independently evolving node representations, enabling fragment nodes to aggregate atom-level and bond-level semantics on an equal footing. We design three level-specific pretraining objectives: an atom-bond cross-view contrastive task that aligns the atom-view and bond-view representations within each fragment, a fragment-level functional group prediction task to inject domain-relevant chemical knowledge, and graph-level structure prediction tasks to encode global molecular topology. Experiments on nine MoleculeNet benchmarks demonstrate that MolCHG achieves the best performance on seven datasets across both classification and regression tasks, remaining competitive with the strongest baselines on the rest. Ablation studies further confirm that the multi-level supervision signals are complementary and that each component contributes to the overall performance.

Fragment-level representations provide a natural way to capture recurring molecular substructures and reuse their learned representations across molecules. However, a shared fragment identity alone may not fully describe how a fragment is instantiated in a particular molecule, since the same fragment can exhibit different chemical behavior depending on its surrounding atomic environment. Effective fragment-based molecular learning therefore requires representations that are both reusable across molecules and sensitive to local atomic context. We introduce BiScale-GTR, a self-supervised molecular representation framework built around context-grounded shared fragment tokens. BiScale-GTR constructs a reusable graph Byte Pair Encoding (graph-BPE) vocabulary using Weisfeiler-Lehman (WL)-based fragment identity, chemical validity filtering, and recursive out-of-vocabulary (OOV) decomposition. Each shared fragment token is then grounded with atom-level GNN representations through atom-to-fragment pooling and gated fusion, allowing the same fragment identity to acquire context-dependent representations in different molecular environments. A structure-aware fragment Transformer performs global reasoning over these atom-grounded tokens, capturing reusable substructure identity, local chemical context, and long-range molecular dependencies. Experiments on MoleculeNet, PharmaBench, and the Long Range Graph Benchmark demonstrate strong performance across classification and regression tasks. Attribution analysis further shows that BiScale-GTR highlights chemically meaningful recurring motifs, providing interpretable links between molecular structure and predicted properties.

Self-supervised pretraining has transformed language and vision, but its value for molecular graph neural networks remains contested. We ask whether pretraining on a large unlabelled corpus improves molecular property prediction. We adapt LeJEPA, a predictor-free joint-embedding predictive architecture regularised by Sketched Isotropic Gaussian Regularisation (SIGReg), to molecular graphs, evaluating GPS and Chemprop-style D-MPNN encoders on the Wong et al. [1] antibiotic-activity dataset and ogbg-molhiv using a multi-seed, bootstrap-based protocol. Pretraining improves learned representations but does not robustly improve finetuning. A frozen probe on pretrained embeddings exceeds random initialisation on both tasks (ogbg-molhiv ROC-AUC 0.788 vs 0.665; +0.123), reaching the published self-supervised band, but this does not translate into finetuning gains. On the antibiotic scaffold split, a canonical partition is significant (delta AUPRC +0.041, p = 0.010), but the effect vanishes across five partitions (pooled +0.013, p = 0.095). Finetuning is null on the random split, ogbg-molhiv, and D-MPNN. The representational edge is nevertheless recoverable. Embeddings saturate at ~16-32 effective dimensions, whereas Morgan fingerprints improve to 1024 bits. At matched dimensionality, fingerprints lead validation (0.799 vs 0.782 at 128 dimensions) but trail shifted test scaffolds (0.759 vs 0.788). Truncating embeddings and combining them with a 1024-bit Morgan fingerprint raises ogbg-molhiv ROC-AUC from 0.805 to 0.832 (delta +0.027; 95% CI [+0.003, +0.054]; p = 0.014); an untrained encoder gains nothing (delta -0.003). Thus, pretraining supplies complementary information best realised through feature-level combination, while finetuning gains are weak and partition-dependent.