{"department":[{"_id":"PaSc"},{"_id":"AlBr"},{"_id":"GradSch"}],"title":"Experiment-guided AlphaFold3 resolves measurement-consistent protein ensembles","quality_controlled":"1","doi":"10.1038/s41587-026-03166-5","corr_author":"1","article_processing_charge":"Yes (via OA deal)","das_tickbox":"1","author":[{"first_name":"Sai A","full_name":"Maddipatla, Sai A","last_name":"Maddipatla","id":"e957f5e5-91c9-11f0-a95f-e090f66ecb4d"},{"last_name":"Sellam","id":"ef280fe0-91c9-11f0-a95f-8dea3f5bc513","first_name":"Nadav E","full_name":"Sellam, Nadav E"},{"first_name":"Meital I","full_name":"Bojan, Meital I","last_name":"Bojan","id":"11d88cf5-91ca-11f0-a95f-edf9f08f47b7"},{"id":"ff7958eb-91c9-11f0-a95f-f3bf65828cf6","last_name":"Masalitin","full_name":"Masalitin, Vova","first_name":"Vova"},{"last_name":"Vedula","first_name":"Sanketh","full_name":"Vedula, Sanketh"},{"orcid":"0000-0002-9350-7606","id":"7B541462-FAF6-11E9-A490-E8DFE5697425","last_name":"Schanda","full_name":"Schanda, Paul","first_name":"Paul"},{"first_name":"Ailie","full_name":"Marx, Ailie","last_name":"Marx"},{"last_name":"Bronstein","id":"58f3726e-7cba-11ef-ad8b-e6e8cb3904e6","orcid":"0000-0001-9699-8730","first_name":"Alexander","full_name":"Bronstein, Alexander"}],"day":"29","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_published":"2026-06-29T00:00:00Z","PlanS_conform":"1","year":"2026","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"epub_ahead","dataavailabilitystatement":"All structures and metrics reported in this paper are openly available on Harvard Dataverse - https://doi.org/10.7910/DVN/PLYUHN. All code is openly available on GitHub (https://github.com/sai-advaith/guided_alphafold); the version used for this paper (version 0.9.1) is permanently archived on Zenodo https://doi.org/10.5281/zenodo.17307005","scopus_import":"1","pmid":1,"status":"public","acknowledgement":"A. Marx acknowledges the financial support of the Helmsley Fellowships Program for Sustainability and Health. A.M.B. and P.S. are supported by the Institute of Science and Technology Austria Internal Project Call grant Generative Protein NMR. S.V. was supported in part by funding from the Eric and Wendy Schmidt Center at the Broad Institute of MIT and Harvard. Open access funding provided by Institute of Science and Technology (IST Austria).","language":[{"iso":"eng"}],"external_id":{"pmid":["42374114"]},"month":"06","abstract":[{"text":"AlphaFold3 predicts highly accurate protein structures from sequence but tends to collapse to a single dominant conformation, even when the underlying structure is inherently heterogeneous. Moreover, its predictions are oblivious to experimental conditions that can alter local sequence conformation. In this work, we show that AlphaFold3 can be guided to match data obtained by nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography and cryogenic electron microscopy (cryo-EM) experiments and combinations thereof. Our approach can also incorporate data that explicitly report on dynamics, such as site-resolved order parameters. We demonstrate that this methodology generates compact structural ensembles whose ensemble-averaged observables agree with experiment, with fewer distance restraint violations than traditionally resolved NMR structures and with unmodeled alternate conformations uncovered in electron density. This methodology paves the way for experimentally aware predictive models that generate structural ensembles consistent with the measurements, potentially over multiple modalities, and that can be further refined toward thermodynamically grounded ensembles by incorporating energetics.","lang":"eng"}],"_id":"22268","has_accepted_license":"1","OA_place":"publisher","type":"journal_article","article_type":"original","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1038/s41587-026-03166-5"}],"publication_identifier":{"issn":["1087-0156"],"eissn":["1546-1696"]},"ddc":["570"],"date_created":"2026-07-12T22:02:19Z","citation":{"ista":"Maddipatla SA, Sellam NE, Bojan MI, Masalitin V, Vedula S, Schanda P, Marx A, Bronstein AM. 2026. Experiment-guided AlphaFold3 resolves measurement-consistent protein ensembles. Nature Biotechnology.","chicago":"Maddipatla, Sai A, Nadav E Sellam, Meital I Bojan, Vova Masalitin, Sanketh Vedula, Paul Schanda, Ailie Marx, and Alex M. Bronstein. “Experiment-Guided AlphaFold3 Resolves Measurement-Consistent Protein Ensembles.” <i>Nature Biotechnology</i>. Springer Nature, 2026. <a href=\"https://doi.org/10.1038/s41587-026-03166-5\">https://doi.org/10.1038/s41587-026-03166-5</a>.","apa":"Maddipatla, S. A., Sellam, N. E., Bojan, M. I., Masalitin, V., Vedula, S., Schanda, P., … Bronstein, A. M. (2026). Experiment-guided AlphaFold3 resolves measurement-consistent protein ensembles. <i>Nature Biotechnology</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41587-026-03166-5\">https://doi.org/10.1038/s41587-026-03166-5</a>","ama":"Maddipatla SA, Sellam NE, Bojan MI, et al. Experiment-guided AlphaFold3 resolves measurement-consistent protein ensembles. <i>Nature Biotechnology</i>. 2026. doi:<a href=\"https://doi.org/10.1038/s41587-026-03166-5\">10.1038/s41587-026-03166-5</a>","ieee":"S. A. Maddipatla <i>et al.</i>, “Experiment-guided AlphaFold3 resolves measurement-consistent protein ensembles,” <i>Nature Biotechnology</i>. Springer Nature, 2026.","mla":"Maddipatla, Sai A., et al. “Experiment-Guided AlphaFold3 Resolves Measurement-Consistent Protein Ensembles.” <i>Nature Biotechnology</i>, Springer Nature, 2026, doi:<a href=\"https://doi.org/10.1038/s41587-026-03166-5\">10.1038/s41587-026-03166-5</a>.","short":"S.A. Maddipatla, N.E. Sellam, M.I. Bojan, V. Masalitin, S. Vedula, P. Schanda, A. Marx, A.M. Bronstein, Nature Biotechnology (2026)."},"OA_type":"hybrid","publication":"Nature Biotechnology","publisher":"Springer Nature","oa_version":"Published Version","supplementarymaterial":"yes","researchdata_availability":"yes","oa":1,"date_updated":"2026-07-13T09:34:36Z"}