Real-time repository-scale spectral search and global molecular networking with HNSW-MS

Abstract

Spectral similarity comparison is the basis of mass spectrometry-based metabolomics, underpinning library matching, molecular network construction, and repository searches such as MASST. Public repositories now exceed billion spectra, and exhaustive pairwise comparison is increasingly limiting. We introduce HNSW-MS, which implements Hierarchical Navigable Small World graph indexing natively for mass spectra. It operates directly on GC-MS and LC-MS/MS spectra without embedding, so scores are identical to those of exhaustive comparison and results are fully reproducible. On the benchmark dataset of 8.4 million LC-MS/MS spectra, HNSW-MS is up to 900-fold faster than linear search, recall@1 and recall@10 achieve over 90%, with the recall-speedup tradeoff tunable at query. Such rapid retrieval allows for any query spectrum to be near-instantaneously integrated into a global molecular network. We demonstrate specific examples of use of global networking for molecular discovery, including uncovering a new pathway of stenothricin biosynthesis and a new dipeptide conjugate bile acid.