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Here, we sought to investigate its mechanism using molecular dynamics simulations. To achieve this, we first constructed the amino-acid-residue-resolution structural models of the cohesin subunits, SMC1, SMC3, STAG1, and NIPBL. By simulating these subunits with double-stranded DNA molecules, we predicted DNA binding patches on each subunit and quantified the affinities of these patches to DNA using their dissociation rate constants as a proxy. Then, we constructed the structural model of the whole cohesin complex and mapped the predicted high-affinity DNA binding patches on the structure. From the spatial relations of the predicted patches, we identified that multiple patches on the SMC1, SMC3, STAG1, and NIPBL subunits form a DNA clamping patch group. The simulations of the whole complex with double-stranded DNA molecules suggest that this patch group facilitates DNA bending and helps capture a DNA segment in the cohesin ring formed by the SMC1 and SMC3 subunits. In previous studies, these have been identified as critical steps in DNA loop extrusion. Therefore, this study provides experimentally testable predictions of DNA binding sites implicated in previously proposed DNA loop extrusion mechanisms and highlights the essential roles of the accessory subunits STAG1 and NIPBL in the mechanism.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012493","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T14:15:04Z","timestamp":1743776104000},"page":"e1012493","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular dynamics simulations of human cohesin subunits identify DNA binding sites and their potential roles in DNA loop extrusion"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0267-0812","authenticated-orcid":true,"given":"Chenyang","family":"Gu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoji","family":"Takada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni B.","family":"Brandani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0151-1123","authenticated-orcid":true,"given":"Tsuyoshi","family":"Terakawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,4,4]]},"reference":[{"issue":"24","key":"pcbi.1012493.ref001","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.15252\/embj.201798004","article-title":"Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins","volume":"36","author":"G Wutz","year":"2017 Dec 15","journal-title":"EMBO J"},{"issue":"5950","key":"pcbi.1012493.ref002","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1126\/science.1181369","article-title":"Comprehensive mapping of long-range interactions reveals folding principles of the human genome","volume":"326","author":"E Lieberman-Aiden","year":"2009 Oct 9","journal-title":"Science"},{"issue":"1","key":"pcbi.1012493.ref003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s42003-023-04819-w","article-title":"Topologically associating domain boundaries are required for normal genome function","volume":"6","author":"S Rajderkar","year":"2023 Apr 20","journal-title":"Commun Biol"},{"issue":"1","key":"pcbi.1012493.ref004","doi-asserted-by":"crossref","first-page":"5415","DOI":"10.1038\/s41467-021-25604-5","article-title":"CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression","volume":"12","author":"M Franke","year":"2021 Sep 13","journal-title":"Nat Commun"},{"issue":"21","key":"pcbi.1012493.ref005","doi-asserted-by":"crossref","first-page":"R1266","DOI":"10.1016\/j.cub.2018.08.034","article-title":"Towards a unified model of SMC complex function","volume":"28","author":"M Hassler","year":"2018 Nov 5","journal-title":"Curr Biol"},{"issue":"7180","key":"pcbi.1012493.ref006","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/nature06634","article-title":"Cohesin mediates transcriptional insulation by CCCTC-binding factor","volume":"451","author":"KS Wendt","year":"2008 Feb","journal-title":"Nature"},{"issue":"6471","key":"pcbi.1012493.ref007","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1126\/science.aaz3418","article-title":"DNA loop extrusion by human cohesin","volume":"366","author":"IF Davidson","year":"2019 Dec 13","journal-title":"Science"},{"issue":"6471","key":"pcbi.1012493.ref008","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1126\/science.aaz4475","article-title":"Human cohesin compacts DNA by loop extrusion","volume":"366","author":"Y Kim","year":"2019 Dec 13","journal-title":"Science"},{"issue":"21","key":"pcbi.1012493.ref009","doi-asserted-by":"crossref","first-page":"5448","DOI":"10.1016\/j.cell.2021.09.016","article-title":"Cohesin mediates DNA loop extrusion by a \u201cswing and clamp\u201d mechanism","volume":"184","author":"BW Bauer","year":"2021 Oct","journal-title":"Cell"},{"issue":"11","key":"pcbi.1012493.ref010","doi-asserted-by":"crossref","first-page":"105296","DOI":"10.1016\/j.jbc.2023.105296","article-title":"High-speed AFM imaging reveals DNA capture and loop extrusion dynamics by cohesin-NIPBL","volume":"299","author":"P Kaur","year":"2023 Nov 1","journal-title":"J Biol Chem"},{"key":"pcbi.1012493.ref011","doi-asserted-by":"crossref","first-page":"e30000","DOI":"10.7554\/eLife.30000","article-title":"Scc2\/Nipbl hops between chromosomal cohesin rings after loading. 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