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A further challenge is to discover the proteins\u2019 orientation as each protein is randomly oriented when exposed to x-rays. Algorithms such as the expand, maximize, and compress (EMC) exist that can solve the orientation problem and reconstruct the three-dimensional diffraction intensity space, given sufficient measurements. If information about orientation were known, for example, by using an electric field to orient the particles, the reconstruction would benefit and potentially reach better results. We used simulated diffraction experiments to test how the reconstructions from EMC improve with particles\u2019 orientation to a preferred axis. Our reconstructions converged to correct maps of the three-dimensional diffraction space with fewer measurements if biased orientation information was considered. Even for a moderate bias, there was still significant improvement. Biased orientations also substantially improved the results in the case of missing central information, in particular in the case of small datasets. The effects were even more significant when adding a background with 50% the strength of the averaged diffraction signal photons to the diffraction patterns, sometimes reducing the data requirement for convergence by a factor of 10. This demonstrates the usefulness of having biased orientation information in single particle imaging experiments, even for a weaker bias than what was previously known. This could be a key component in overcoming the problems with background noise that currently plague these experiments.<\/jats:p>","DOI":"10.1063\/5.0188772","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T10:13:31Z","timestamp":1710929611000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Enhanced EMC\u2014Advantages of partially known orientations in x-ray single particle imaging"],"prefix":"10.1063","volume":"160","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5568-5017","authenticated-orcid":false,"given":"August","family":"Wollter","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Biology, Laboratory of Molecular Biophysics 1 , Husargatan 3, 75124 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-7429","authenticated-orcid":false,"given":"Emiliano","family":"De Santis","sequence":"additional","affiliation":[{"name":"Department of Chemistry\u2014BMC, Uppsala University 2 , Box 576, SE-751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0092-2104","authenticated-orcid":false,"given":"Tomas","family":"Ekeberg","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, Laboratory of Molecular Biophysics 1 , Husargatan 3, 75124 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9804-5009","authenticated-orcid":false,"given":"Erik G.","family":"Marklund","sequence":"additional","affiliation":[{"name":"Department of Chemistry\u2014BMC, Uppsala University 2 , Box 576, SE-751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2638-1940","authenticated-orcid":false,"given":"Carl","family":"Caleman","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, Uppsala University 3 , Box 516, SE-751 20 Uppsala, Sweden"},{"name":"Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY 4 , Notkestra\u00dfe 85, DE-22607 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2024,3,20]]},"reference":[{"key":"2024032010132143000_c1","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1038\/35021099","article-title":"Potential for biomolecular imaging with femtosecond X-ray pulses","volume":"406","year":"2000","journal-title":"Nature"},{"key":"2024032010132143000_c2","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/nature09748","article-title":"Single mimivirus particles intercepted and imaged with an x-ray laser","volume":"470","year":"2011","journal-title":"Nature"},{"key":"2024032010132143000_c3","doi-asserted-by":"publisher","first-page":"098102","DOI":"10.1103\/physrevlett.114.098102","article-title":"Three-dimensional reconstruction of the giant mimivirus particle with an x-ray free-electron laser","volume":"114","year":"2015","journal-title":"Phys. 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