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Here, we describe a generative artificial intelligence method for biopolymers, RFdiffusion3 (RFD3), which employs free atom diffusion to satisfy complex sets of atomic constraints more rapidly and accurately than previous methods across several challenges from enzyme design to RNA structure design. We demonstrate experimentally the power of the RFD3 pipeline for enzyme design by designing de novo phosphotriesterases with a complex active site architecture incorporating a carbamylated lysine coordinating two metal ions and zinc proteases specific for the transthyretin protein involved in amyloid diseases; in both cases we obtain active catalysts in zero shot 96 construct design campaigns.<\/jats:p>","DOI":"10.1126\/science.aeh2982","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:01:27Z","timestamp":1792087287000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Atomic functional site scaffolding in biopolymers with RFdiffusion3"],"prefix":"10.1126","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4864-1330","authenticated-orcid":true,"given":"Jasper","family":"Butcher","sequence":"first","affiliation":[{"name":"Institute for Protein Design, University of Washington, Seattle, WA, USA."},{"name":"Department of Biochemistry, University of Washington, Seattle, WA, USA."},{"name":"Paul G. 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Wang De novo design of high-affinity protein binders with AlphaProteo. arXiv:2409.08022 [q-bio.BM] (12 September 2024)."},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn2100"},{"key":"e_1_3_2_11_2","doi-asserted-by":"crossref","unstructured":"Chai Discovery Team J. Boitreaud J. Dent D. Geisz M. McPartlon J. Meier Z. Qiao A. Rogozhnikov N. Rollins P. Wollenhaupt K. Wu Zero-shot antibody design in a 24-well plate. bioRxiv 2025.07.05.663018 [Preprint] (2025); https:\/\/doi.org\/10.1101\/2025.07.05.663018.","DOI":"10.1101\/2025.07.05.663018"},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","unstructured":"Y. Cho G. Rangel G. Bhardwaj S. Ovchinnikov Protein Hunter: exploiting structure hallucination within diffusion for protein design. bioRxiv 2025.10.10.681530 [Preprint] (2025); https:\/\/doi.org\/10.1101\/2025.10.10.681530.","DOI":"10.1101\/2025.10.10.681530"},{"key":"e_1_3_2_13_2","doi-asserted-by":"crossref","unstructured":"M. Fang C. Wang J. Shi F. 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