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Rev. Lett."],"accepted":{"date-parts":[[2026,5,19]]},"abstract":"<jats:p>Single-molecule force spectroscopy resolves folding dynamics one molecule at a time, but extracting quantitative free-energy landscapes typically requires extensive datasets and careful instrument calibration to disentangle the molecule from linker and apparatus artifacts. We introduce a simulation-based inference framework that combines physics-based modeling with deep learning to recover the Bayesian posterior of a folding model directly from a single short trajectory. A 2-s constant-force measurement of a DNA hairpin is sufficient to reconstruct the folding landscape, matching deconvolution baselines that require 20\u2013100 times more data and eliminating separate linker or instrument characterization. The same approach recovers four metastable states of a riboswitch aptamer from a single 5-s trajectory. Every parameter, including diffusion coefficients and linker stiffness, is included in the calibrated posterior. The current implementation assumes one-dimensional Markovian dynamics, but more complex models can be substituted within the same framework, opening single-molecule force spectroscopy to high-throughput parallel experiments and to systems where extensive data collection is impractical.<\/jats:p>","DOI":"10.1103\/yltb-6jkj","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:34:33Z","timestamp":1779201273000},"update-policy":"https:\/\/doi.org\/10.1103\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Quantitative and Predictive Folding Models from Limited Single-Molecule Data Using Simulation-Based Inference"],"prefix":"10.1103","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9623-1943","authenticated-orcid":true,"given":"Lars","family":"Dingeldein","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04cvxnb49","id-type":"ROR","asserted-by":"publisher"}],"name":"Goethe University Frankfurt"},{"id":[{"id":"https:\/\/ror.org\/05vmv8m79","id-type":"ROR","asserted-by":"publisher"}],"name":"Frankfurt Institute for Advanced Studies"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Lyons","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0160cpw27","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Alberta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5404-9948","authenticated-orcid":true,"given":"Pilar","family":"Cossio","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00sekdz59","id-type":"ROR","asserted-by":"publisher"}],"name":"Flatiron Institute"},{"id":[{"id":"https:\/\/ror.org\/00sekdz59","id-type":"ROR","asserted-by":"publisher"}],"name":"Flatiron Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Woodside","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0160cpw27","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Alberta"},{"id":[{"id":"https:\/\/ror.org\/0160cpw27","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Alberta"},{"id":[{"id":"https:\/\/ror.org\/0160cpw27","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Alberta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0884-0402","authenticated-orcid":true,"given":"Roberto","family":"Covino","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04cvxnb49","id-type":"ROR","asserted-by":"publisher"}],"name":"Goethe University Frankfurt"},{"id":[{"id":"https:\/\/ror.org\/05vmv8m79","id-type":"ROR","asserted-by":"publisher"}],"name":"Frankfurt Institute for Advanced Studies"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"yltb-6jkjCc1R1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1219021","type":"journal-article"},{"key":"yltb-6jkjCc2R1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0197-10","type":"journal-article"},{"key":"yltb-6jkjCc3R1","doi-asserted-by":"crossref","DOI":"10.1002\/9783527619498","type":"book","volume-title":"Protein Folding Handbook","author":"J. 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All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright_statement","label":"Copyright statement","group":{"name":"copyright","label":"copyright"}},{"value":"2026","name":"copyright_year","label":"Copyright year","group":{"name":"copyright","label":"copyright"}},{"value":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/","name":"creative_commons_license","label":"Creative Commons license","group":{"name":"licenses","label":"Licenses"}},{"value":"\u00a92026 The authors","name":"copyright_holder","label":"Copyright holder","group":{"name":"copyright","label":"copyright"}}],"article-number":"088402"}}