Title: Learning the Neighborhood: Contrast-Free Multimodal Self-Supervised Molecular Graph Pretraining
Primary area: learning on graphs and other geometries & topologies
Keywords: Pretraining, Graph, Self, Supervised, Non, Contrastive, SSL, Self, Predictive, Molecular, Foundation, Model, Multimodal, Conformers

Abstract: High-quality molecular representations are essential for property prediction and molecular design, yet large labeled datasets remain scarce. While self-supervised pretraining on molecular graphs has shown promise, many existing approaches either depend on hand-crafted augmentations or complex generative objectives, and often rely solely on 2D topology, leaving valuable 3D structural information underutilized. To address this gap, we introduce C-FREE (Contrast-Free Representation learning on Ego-nets), a simple framework that integrates 2D graphs with ensembles of 3D conformers. C-FREE learns molecular representations by predicting subgraph embeddings from their complementary neighborhoods in the latent space, using fixed-radius ego-nets as modeling units across different conformers. This design allows us to integrate both geometric and topological information within a hybrid Graph Neural Network (GNN)-Transformer backbone, without negatives, positional encodings, or expensive pre-processing. Pretraining on the GEOM dataset, which provides rich 3D conformational diversity, C-FREE achieves state-of-the-art results on MoleculeNet, surpassing contrastive, generative, and other multimodal self-supervised methods. Fine-tuning across datasets with diverse sizes and molecule types further demonstrates that pretraining transfers effectively to new chemical domains, highlighting the importance of 3D-informed molecular representations.

TL;DR: C-FREE is a simple self-supervised framework that jointly leverages 2D graphs and 3D conformers to learn molecular representations without negatives, achieving state-of-the-art results and strong transfer across chemical domains.