Multimodal Molecular Representation Learning with Graph Neural Networks, Deep & Cross Networks, and SMILES Embeddings
Authors: Qiwei Han, Chi Zhou, Ruobing Wang, Zheng Ma
Organizations: Department of Chemistry, Duke University, Durham, NC 27708, USA · Department of Computer Science, Georgia Institute of Technology, Atlanta, GA 30332, USA
Abstract
Molecular property prediction often relies on isolated data modalities, where continuous 3D graph neural networks (GNNs) struggle to efficiently capture long-range topological dependencies and exact macroscopic heuristics. In this work, we introduce a parameter-efficient Tri-Branch Modular Fusion Neural Network that synthesizes three orthogonal modalities: 3D spatial geometry (SchNet), discrete topological grammar (SMILES via ChemBERTa), and explicit macroscopic physicochemical descriptors (Deep & Cross Network). By bypassing standard scalar readouts and employing a shared late-fusion architecture, the framework establishes a mathematically rigorous multimodal latent space that effectively resolves the arithmetic and oversmoothing limitations of local message passing. We evaluate the proposed architecture on the QM9 benchmark, targeting the extensive thermodynamic property of atomization energy at 0 K (U0atom). Through systematic combinatorial ablation and latent bottleneck optimization (de=64), the tri-modal framework achieves a validation Mean Absolute Error (MAE) of 0.0207 eV. Operating with fewer than one million parameters, this architecture decisively surpasses the sub-chemical accuracy threshold and yields a substantial 20.6% error reduction over a strictly controlled geometric baseline. Ultimately, our findings demonstrate that integrating orthogonal macroscopic and topological data streams provides a synergistic, O(1) physical shortcut. This multimodal alignment offers a highly efficient alternative to brute-force parameter scaling, establishing a robust surrogate model for high-throughput virtual screening (HTVS) pipelines.
Deep learning models facilitate the discovery of molecules with tailored properties among billions of candidate compounds. However, the computational burden to develop and deploy state-of-the-art models continuously increases, limiting their scalability. Most large-scale models are unimodal in nature and overlook the potential to leverage complementary molecular data modalities. To address these shortcomings, this paper introduces the Graph-Language Alignment for Chemical Inference and Exploration using Representations (GLACIER) model, a student-teacher framework that integrates molecular graphs, SMILES strings, and physicochemical descriptors to learn rich molecular embeddings. Our framework consists of three stages: (1) we pretrain three student encoders on 100,000 drug-like molecules: a message-passing neural network for molecular graphs, a transformer-based encoder for SMILES strings, and a multilayer perceptron for physicochemical descriptors, (2) we fuse these student modalities using a novel Finsler geometry-aware module, and (3) distill complementary knowledge from large teacher models, including MiniMol and MolFormer, into a single lightweight model via contrastive learning. We demonstrate that GLACIER is a robust framework that delivers high predictive performance and computational efficiency in complex molecular property prediction tasks. Our code is publicly available at https://github.com/eemokey/glacier.
Molecular message-passing neural networks commonly propagate chemically diverse interactions through a single graph, which may mix interaction-specific signals and require deep propagation to capture long-range effects. We introduce the Multi-level, Multi-color Graph Neural Network (MMGNN), a hierarchical framework that decomposes a molecular graph into overlapping atom-type-pair-specific subgraphs while preserving atom-level resolution. MMGNN-2D constructs chemical-colored subgraphs from covalent connectivity, whereas MMGNN-3D constructs geometric-colored subgraphs from spatial proximity and augments their edges with distance, angular, and torsional descriptors. Both variants apply a shared communicative message-passing backbone to each subgraph and combine the resulting representations through atom-wise aggregation and molecular readout. We evaluated MMGNN on five classification and three regression benchmarks from MoleculeNet using common scaffold splits and five independent runs. MMGNN-2D achieved the highest macro-average AUC-ROC of 0.838 across the classification datasets and the lowest RMSE on ESOL (0.803). MMGNN-3D obtained the highest mean AUC-ROC on BBBP (0.956) and the lowest RMSE on FreeSolv (1.793), indicating complementary strengths of topological and geometric representations. Structural and leave-one-out analyses further illustrate how the subgraph decomposition affects learned representations and atom-type-pair sensitivities. These results support overlapping interaction-specific graph decomposition as a competitive strategy for molecular property prediction.
Molecular property prediction requires representations that generalize from limited labeled data to structurally novel compounds. Existing molecular pretraining methods often rely on a single view: graph-based approaches model atom-bond topology but provide limited fragment-level supervision, whereas fingerprint descriptors encode chemical patterns but are typically used as fixed auxiliary features. We propose HiFi-Mol, a multi-view framework that separately pretrains a hierarchical graph encoder and a contextualized fingerprint encoder before downstream integration. The graph branch uses fragment-aware masking with multi-resolution supervision to capture substructure-aware representations, while the fingerprint branch tokenizes active entries from seven fingerprint families and applies masked language modeling to learn contextualized embeddings. During fine-tuning, HiFi-Mol combines projected multi-resolution graph features with fingerprint embeddings for downstream prediction. Evaluated on MoleculeNet benchmarks under the scaffold split, HiFi-Mol achieves a 2.77% improvement in average ROC-AUC over the best baseline across eight classification tasks while maintaining competitive performance on three regression tasks. Further analyses reveal that fragment-aware masking improves graph representation quality, and classification results demonstrate dataset-dependent strengths of the individual graph and fingerprint variants, confirming that the two views provide complementary predictive signals.