Contextual AI models for single-cell protein biology

Abstract

Understanding protein function and developing molecular therapies require deciphering the cell types in which proteins act as well as the interactions between proteins. However, modeling protein interactions across biological contexts remains challenging for existing algorithms. Here, we introduce PO_SCPLOWINNACLEC_SCPLOW, a geometric deep learning approach that generates context-aware protein representations. Leveraging a multi-organ single-cell atlas, PO_SCPLOWINNACLEC_SCPLOW learns on contextualized protein interaction networks to produce 394,760 protein representations from 156 cell type contexts across 24 tissues. PO_SCPLOWINNACLEC_SCPLOWs embedding space reflects cellular and tissue organization, enabling zero-shot retrieval of the tissue hierarchy. Pretrained protein representations can be adapted for downstream tasks: enhancing 3D structure-based representations for resolving immuno-oncological protein interactions, and investigating drugs effects across cell types. PO_SCPLOWINNACLEC_SCPLOW outperforms state-of-the-art models in nominating therapeutic targets for rheumatoid arthritis and inflammatory bowel diseases, and pinpoints cell type contexts with higher predictive capability than context-free models. PO_SCPLOWINNACLEC_SCPLOWs ability to adjust its outputs based on the context in which it operates paves way for large-scale context-specific predictions in biology.