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During a typical perturbative crystallography experiment, only a fraction of protein molecules in a crystal will be perturbed, or \u201cexcited\u201d. As a result, the observed data represent a mixture of excited and ground states. The conventional approach to estimating the excited-state structure factor amplitudes is to linearly extrapolate the difference between the structure factor amplitudes of the perturbed and unperturbed data. This approach often fails to yield well-refined structural models because it amplifies experimental errors and neglects phase differences between the ground and excited states. Here, we introduce an approach to estimating excited-state structure factor amplitudes that starts from a statistical prior for the correlations between excited and ground states. Using benchmarks from time-resolved crystallography and a drug-fragment screen, we illustrate how this approach effectively addresses the limitations of traditional extrapolation.<\/jats:p>","DOI":"10.64898\/2026.04.16.719053","type":"posted-content","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T19:55:18Z","timestamp":1776801318000},"source":"Crossref","is-referenced-by-count":0,"title":["Inferring structure factors of weakly populated excited states in perturbative crystallography experiments"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8367-5622","authenticated-orcid":false,"given":"Andrew K.","family":"Choe","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4275-9472","authenticated-orcid":false,"given":"Harrison K.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138"},{"name":"Graduate Program in Biophysics, Harvard University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2332-9223","authenticated-orcid":false,"given":"Doeke R.","family":"Hekstra","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138"},{"name":"John A. 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