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In XL-MS experiments, proteins are cross-linked by a chemical reagent (namely cross-linker), fragmented, and then fed into a tandem mass spectrum (MS\/MS). Cross-linkers are either cleavable or non-cleavable, and each type requires distinct data analysis tools. However, both types of cross-linkers suffer from imbalanced fragmentation efficiency, resulting in a large number of unidentifiable spectra that hinder the discovery of PPIs and protein conformations. To address this challenge, researchers have sought to improve the sensitivity of XL-MS through invention of novel cross-linking reagents, optimization of sample preparation protocols, and development of data analysis algorithms. One promising approach to developing new data analysis methods is to apply a protein feedback mechanism in the analysis. It has significantly improved the sensitivity of analysis methods in the cleavable cross-linking data. The application of the protein feedback mechanism to the analysis of non-cleavable cross-linking data is expected to have an even greater impact because the majority of XL-MS experiments currently employs non-cleavable cross-linkers.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In this study, we applied the protein feedback mechanism to the analysis of both non-cleavable and cleavable cross-linking data and observed a substantial improvement in cross-link spectrum matches (CSMs) compared to conventional methods. Furthermore, we developed a new software program, ECL 3.0, that integrates two algorithms and includes a user-friendly graphical interface to facilitate wider applications of this new program.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>ECL 3.0 source code is available at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/yuweichuan\/ECL-PF.git\">https:\/\/github.com\/yuweichuan\/ECL-PF.git<\/jats:ext-link>. A quick tutorial is available at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/youtu.be\/PpZgbi8V2xI\">https:\/\/youtu.be\/PpZgbi8V2xI<\/jats:ext-link>.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12859-023-05473-z","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T09:02:08Z","timestamp":1695200528000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["ECL 3.0: a sensitive peptide identification tool for cross-linking mass spectrometry data analysis"],"prefix":"10.1186","volume":"24","author":[{"given":"Chen","family":"Zhou","sequence":"first","affiliation":[]},{"given":"Shuaijian","family":"Dai","sequence":"additional","affiliation":[]},{"given":"Shengzhi","family":"Lai","sequence":"additional","affiliation":[]},{"given":"Yuanqiao","family":"Lin","sequence":"additional","affiliation":[]},{"given":"Xuechen","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[]},{"given":"Weichuan","family":"Yu","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"key":"5473_CR1","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1021\/acs.analchem.7b04431","volume":"90","author":"C Yu","year":"2018","unstructured":"Yu C, Huang L. 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All authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"351"}}