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Fundamental to this approach is a multilateration algorithm that harnesses sets of interconnected spin label pairs to identify optimal rotamer ensembles at each residue that fit the DEER decay in the time domain. Benchmarked relative to data analysis packages, the algorithm yields comparable distance distributions with the advantage that fitting the DEER decay and rotamer ensemble optimization are coupled. We demonstrate this approach by modeling the protonation-dependent transition of the multidrug transporter PfMATE to an inward facing conformation with a deviation to the experimental structure of less than 2\u00c5 C<jats:sub>\u03b1<\/jats:sub> RMSD. By decreasing spin label rotamer entropy, this approach engenders more accurate Rosetta models that are also more closely clustered, thus setting the stage for more robust modeling of protein conformational changes.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009107","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T17:32:22Z","timestamp":1623864742000},"page":"e1009107","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":23,"title":["Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1757-9971","authenticated-orcid":true,"given":"Diego","family":"del Alamo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1475-2513","authenticated-orcid":true,"given":"Kevin L.","family":"Jagessar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8945-193X","authenticated-orcid":true,"given":"Jens","family":"Meiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5673-0980","authenticated-orcid":true,"given":"Hassane S.","family":"Mchaourab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"pcbi.1009107.ref001","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/nsmb.2816","article-title":"Conformational dynamics of ligand-dependent alternating access in LeuT","volume":"21","author":"K Kazmier","year":"2014","journal-title":"Nat Struct Mol Biol"},{"key":"pcbi.1009107.ref002","doi-asserted-by":"crossref","first-page":"15324","DOI":"10.1039\/C7CP01925D","article-title":"Rates and equilibrium constants of the ligand-induced conformational transition of an HCN ion channel protein domain determined by DEER spectroscopy","volume":"19","author":"A Collauto","year":"2017","journal-title":"Phys Chem Chem Phys"},{"key":"pcbi.1009107.ref003","doi-asserted-by":"crossref","first-page":"10839","DOI":"10.1073\/pnas.1916375117","article-title":"Stoll S. 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