Learning Molecular Representation in a Cell

Gang Liu, Srijit Seal, John Arevalo, Zhenwen Liang, Anne E Carpenter, Meng Jiang, Shantanu Singh

Keywords: Molecular Representation Learning, Drug Discovery, Cell Morphology, Gene Expression

TL;DR: We propose InfoAlign, a method that learns minimal sufficient molecular representations from cellular response data, including cell morphology and gene expressions.

Abstract: Predicting drug efficacy and safety in vivo requires information on biological responses (e.g., cell morphology and gene expression) to small molecule perturbations. However, current molecular representation learning methods do not provide a comprehensive view of cell states under these perturbations and struggle to remove noise, hindering model generalization. We introduce the Information Alignment (InfoAlign) approach to learn molecular representations through the information bottleneck method in cells. We integrate molecules and cellular response data as nodes into a context graph, connecting them with weighted edges based on chemical, biological, and computational criteria. For each molecule in a training batch, InfoAlign optimizes the encoder's latent representation with a minimality objective to discard redundant structural information. A sufficiency objective decodes the representation to align with different feature spaces from the molecule's neighborhood in the context graph. We demonstrate that the proposed sufficiency objective for alignment is tighter than existing encoder-based contrastive methods. Empirically, we validate representations from InfoAlign in two downstream applications: molecular property prediction against up to 27 baseline methods across four datasets, plus zero-shot molecule-morphology matching. The code and model are available at https://github.com/liugangcode/InfoAlign.

Primary Area: applications to physical sciences (physics, chemistry, biology, etc.)

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Submission Number: 4989