Unified genomic and chemical representations enable bidirectional biosynthetic gene cluster and natural product retrieval

Abstract

Abstract Natural product discovery is increasingly driven by the ability to analyze microbial genomes for biosynthetic gene clusters (BGCs) that encode secondary metabolites. While existing approaches have successfully linked BGCs to broad classes of chemical products, they typically operate in a single modality (genomic or chemical) limiting the scope of bidirectional prediction. In this work, we propose a multimodal framework that integrates genomic and chemical information by projecting embeddings derived from pretrained language models into a common representation space. We embed genomic sequences using a BGC foundation model and represent molecules through a chemical language model, then use a metric learning model to co-embed BGCs and their associated chemical structures. This co-embedding space allows us to quantify the similarity between BGCs and compounds using similarity measures, enabling both efficient forward and inverse retrieval tasks. Our approach consistently outperforms the non-alignment approach and represents a generalizable, scalable strategy to bridge biological and chemical modalities in natural product discovery.