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Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,10]]},"abstract":"<jats:p>Proteins often exhibit subdiffusive configurational dynamics, the origins of which are still unresolved. We investigate the impact of non-Markovian friction and the free-energy landscape on the dynamics of fast-folding proteins in terms of the mean squared displacement (MSD) and the mean first-passage-time (MFPT) of the folding reaction coordinate. We find the friction memory kernel from published molecular dynamics simulations to be well-described by a hierarchical multiexponential function, which gives rise to subdiffusion in the MSD for times shorter than the longest memory time, while for longer times the confining free-energy landscape produces subdiffusion. Thus, for a wide range of times, friction memory effects in fast-folding proteins dominate the scaling behavior of the MSD compared to effects due to the folding free-energy landscape. As a consequence, Markovian models are insufficient to fully capture the folding dynamics, as quantified by the MSD and the MFPT, even when including coordinate-dependent friction. Our results demonstrate the importance of memory effects in protein folding and conformational dynamics and explicitly show that subdiffusion in fast-folding protein dynamics originates mainly from memory effects, not from the free-energy landscape and not from coordinate-dependent friction.<\/jats:p>","DOI":"10.1073\/pnas.2516506123","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T18:48:53Z","timestamp":1770403733000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Hierarchical friction memory leads to subdiffusive configurational dynamics of fast-folding proteins"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5853-3092","authenticated-orcid":false,"given":"Anton","family":"Klimek","sequence":"first","affiliation":[{"name":"Fachbereich Physik","place":["Berlin, Germany"]},{"name":"Freie Universit\u00e4t Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0448-2989","authenticated-orcid":false,"given":"Benjamin A.","family":"Dalton","sequence":"additional","affiliation":[{"name":"Fachbereich Physik","place":["Berlin, Germany"]},{"name":"Freie Universit\u00e4t Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8403-5275","authenticated-orcid":false,"given":"Lucas","family":"Tepper","sequence":"additional","affiliation":[{"name":"Fachbereich Physik","place":["Berlin, Germany"]},{"name":"Freie Universit\u00e4t Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0147-0162","authenticated-orcid":false,"given":"Roland R.","family":"Netz","sequence":"additional","affiliation":[{"name":"Fachbereich Physik","place":["Berlin, Germany"]},{"name":"Freie Universit\u00e4t Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-017-0077-5"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/j100717a029"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408098102"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.6b00163"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21371"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1063\/5.0255498"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct3008292"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-8914(40)90098-2"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar5002999"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct5002363"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023856118"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2220068120"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.94.198302"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.93.180603"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.80.5015"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpclett.8b00956"},{"key":"e_1_3_4_18_2","unstructured":"L. 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