Interpretable adenylation domain specificity prediction using protein language models.

Natural products have long been a rich source of diverse and clinically effective drug candidates. Non-ribosomal peptides (NRPs), polyketides (PKs), and NRP-PK hybrids are three classes of natural products that display a broad range of bioactivities, including antibiotic, antifungal, anticancer, and immunosuppressant activities. However, discovering these compounds through traditional bioactivity-guided techniques is costly and time-consuming, often resulting in the rediscovery of known molecules. Consequently, genome mining has emerged as a high-throughput strategy to screen hundreds of thousands of microbial genomes to identify their potential to produce novel natural products. Adenylation domains play a key role in the biosynthesis of NRPs and NRP-PKs by recruiting substrates to incrementally build the final structure. We propose MASPR, a machine learning method that leverages protein language models for accurate and interpretable predictions of A-domain substrate specificities. MASPR demonstrates superior accuracy and generalization over existing methods and is capable of predicting substrates not present in its training data, or zero-shot classification. We use MASPR to develop Seq2Hybrid, an efficient algorithm to predict the structure of hybrid NRP-PK natural products from microbial genomes. Using Seq2Hybrid, we propose putative biosynthetic gene clusters for the orphan natural products Octaminomycin A, Dityromycin, SW-163B, and JBIR-39.