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Understanding the improved sensitivity of spectral library searching over sequence database searching in proteomics data analysis

Spectral library searching has been recently proposed as an alternative to sequence database searching for peptide identification from MS/MS. We performed a systematic comparison between spectral library searching and sequence database searching using a wide variety of data to better demonstrate, and understand, the superior sensitivity of the former observed in preliminary studies. By decoupling the effect of search space, we demonstrated that the success of spectral library searching is primarily attributable to the use of real library spectra for matching, without which the sensitivity advantage largely disappears. We further determined the extent to which the use of real peak intensities and non‐canonical fragments, both under‐utilized information in sequence database searching, contributes to the sensitivity advantage. Lastly, we showed that spectral library searching is disproportionately more successful in identifying low‐quality spectra, and complex spectra of higher‐ charged precursors, both important frontiers in peptide sequencing. Our results answered important outstanding questions about this promising yet unproven method using well‐controlled computational experiments and sound statistical approaches.