Open Access Repository-Scale Propagated Nearest Neighbor Suspect Spectral Library for Untargeted Metabolomics

Abstract

Despite the increasing availability of tandem mass spectrometry (MS/MS) community spectral libraries for untargeted metabolomics over the past decade, the majority of acquired MS/MS spectra remain uninterpreted. To further aid in interpreting unannotated spectra, we created a nearest neighbor suspect spectral library, consisting of 87,916 annotated MS/MS spectra derived from hundreds of millions of public MS/MS spectra. Annotations were propagated based on structural relationships to reference molecules using MS/MS-based spectrum alignment. We demonstrate the broad relevance of the nearest neighbor suspect spectral library through representative examples of propagation-based annotation of acylcarnitines, bacterial and plant natural products, and drug metabolism. Our results also highlight how the library can help to better understand an Alzheimer’s brain phenotype. The nearest neighbor suspect spectral library is openly available through the GNPS platform to help investigators hypothesize candidate structures for unknown MS/MS spectra in untargeted metabolomics data.

Comparison of Cosine, Modified Cosine, and Neutral Loss Based Spectrum Alignment For Discovery of Structurally Related Molecules

“…Finally, neutral loss matching first transforms MS/MS spectra into neutral loss spectra by mirroring the fragment ion m/z values at precursor m/z = 810.487). 22 We evaluate the cosine similarity (left), modified cosine similarity (middle), and neutral loss matching (right, visualized as neutral loss spectra) to compare MS/MS spectra to each other. Directly matching fragments with near-identical m/z or ∆m/z values in the original MS/MS spectra and the neutral loss spectra, respectively, are indicated in blue.…”

“…( b ) Illustration of the MS/MS spectrum alignment methods applied to the natural product apratoxin A (top; precursor m/z = 840.497) and a newly discovered apratoxin analog (bottom; precursor m/z = 810.487). 22 We evaluate the cosine similarity (left), modified cosine similarity (middle), and neutral loss matching (right, visualized as neutral loss spectra) to compare MS/MS spectra to each other. Directly matching fragments with near-identical m/z or Δ m/z values in the original MS/MS spectra and the neutral loss spectra, respectively, are indicated in blue.…”

“…(a) Spectrum similarity measures are evaluated using large MS/MS datasets drawn from the MassIVE-KB peptide spectral library, the small molecule GNPS community spectral libraries, and the GNPS bile acids library. (b) Illustration of the MS/MS spectrum alignment methods applied to the natural product apratoxin A (top; precursor m/z = 840.497) and a newly discovered apratoxin analog (bottom;precursor m/z = 810.487) 22. We evaluate the cosine similarity (left), modified cosine similarity…”

Effects of a Ketogenic and Low Fat Diet on the Human Metabolome, Microbiome and Food-ome in Adults at Risk for Alzheimer’s Disease

“…We found that one of the top metabolites associated with both the ketogenic diet and cognitive normality was related to curcumol through a nearest-neighbor suspect library (41). Another compound produced by the same plant, curcumin, was instead elevated in participants with MCI who ate the low-fat AHAD diet ( Figure 4F ).…”

MS2Query: Reliable and Scalable MS2 Mass Spectral-based Analogue Search

“…This approach also relies on annotated mass spectral libraries, but aims at finding molecules that are chemically similar, without the need for them to be identical. Current tools able to perform analogue searches often rely on a (modified) cosine score to predict chemical similarity 4,9,21 . However, a limitation of the cosine score (and its derivatives) is that small chemical modifications can, and multiple chemical modifications will, often result in a large decrease in mass spectral similarity which limits its ability to serve as a proxy for chemical similarity [22][23][24] .…”