{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:18:48Z","timestamp":1787681928743,"version":"build-2784847793"},"posted":{"date-parts":[[2026,8,11]]},"group-title":"Bioengineering","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Sciences of the National Institutes of Health","award":["R35GM138201"],"award-info":[{"award-number":["R35GM138201"]}]},{"DOI":"10.13039\/100000774","name":"Defense Threat Reduction Agency","doi-asserted-by":"crossref","award":["HDTRA1-21-1-0014"],"award-info":[{"award-number":["HDTRA1-21-1-0014"]}],"id":[{"id":"10.13039\/100000774","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Biomolecular structure is commonly predicted from sequence as a single structural model, yet many molecules function through conformational ensembles that reorganize with their surroundings. Whether such structural responsiveness can be learned jointly from sequence and environmental context remains unresolved. Here, we use short peptides as an experimentally tractable system to test this principle. We assembled a large experimental multi-environment dataset for peptides\u2019 secondary structure, comprising more than 1,500 peptides and more than 5,500 peptide\u2013environment observations across aqueous, co-solvent, and membrane-mimicking conditions. We developed ApexFold, an environment-conditioned AI framework that combines sequence representations with physicochemical descriptors of the surrounding medium to predict circular-dichroism-derived fractions of\n                  <jats:bold>\n                    <jats:italic>\u03b1<\/jats:italic>\n                  <\/jats:bold>\n                  -helical,\n                  <jats:bold>\n                    <jats:italic>\u03b2<\/jats:italic>\n                  <\/jats:bold>\n                  -like, and unstructured conformations. In two later-collected panels excluded from model development, ApexFold captured the direction and magnitude of environment-induced structural redistribution and the peptide-specific degree of plasticity, while outperforming solvent-agnostic and composition-based baselines. Static structural references, which return a single conformation, cannot represent these condition-dependent response profiles. These results establish structural responsiveness as a learnable property of sequence and environment, extending biomolecular prediction beyond static structure toward predicting\u2014and ultimately designing\u2014how molecules respond to the contexts in which they function.\n                <\/jats:p>","DOI":"10.64898\/2026.08.09.743796","type":"posted-content","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:45:12Z","timestamp":1786437912000},"source":"Crossref","is-referenced-by-count":0,"title":["Peptide structural plasticity is predictable from sequence and environment"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-9138","authenticated-orcid":false,"given":"Marcelo D.T.","family":"Torres","sequence":"first","affiliation":[{"name":"Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104 USA."},{"name":"Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104 USA"},{"name":"Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104 USA."},{"name":"Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA, 19104 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanqun","family":"Cao","sequence":"additional","affiliation":[{"name":"Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104 USA."},{"name":"Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104 USA"},{"name":"Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104 USA."},{"name":"Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA, 19104 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2005-5629","authenticated-orcid":false,"given":"Cesar","family":"de la Fuente-Nunez","sequence":"additional","affiliation":[{"name":"Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104 USA."},{"name":"Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104 USA"},{"name":"Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104 USA."},{"name":"Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA, 19104 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"4","key":"2026082510251068000_2026.08.09.743796v2.1","first-page":"236","article-title":"Mode of action of membrane active antimicrobial peptides. Peptide Science","volume":"66","year":"2002","journal-title":"Original Research on Biomolecules"},{"key":"2026082510251068000_2026.08.09.743796v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2012.03.002"},{"key":"2026082510251068000_2026.08.09.743796v2.3","doi-asserted-by":"crossref","unstructured":"Mahlapuu, M. , H\u00e5kansson, J. , Ringstad, L. , Bj\u00f6rn, C. : Antimicrobial peptides: an emerging category of therapeutic agents. Frontiers in cellular and infection microbiology 6, 194 (2016)","DOI":"10.3389\/fcimb.2016.00194"},{"issue":"6","key":"2026082510251068000_2026.08.09.743796v2.4","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1038\/nprot.2006.202","article-title":"Using circular dichroism spectra to estimate protein secondary structure","volume":"1","year":"2006","journal-title":"Nature protocols"},{"key":"2026082510251068000_2026.08.09.743796v2.5","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2000.4880"},{"key":"2026082510251068000_2026.08.09.743796v2.6","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky497"},{"key":"2026082510251068000_2026.08.09.743796v2.7","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa991"},{"key":"2026082510251068000_2026.08.09.743796v2.8","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaf860"},{"key":"2026082510251068000_2026.08.09.743796v2.9","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1046"},{"key":"2026082510251068000_2026.08.09.743796v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2025.02.007"},{"key":"2026082510251068000_2026.08.09.743796v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrp.2023.101459"},{"key":"2026082510251068000_2026.08.09.743796v2.12","doi-asserted-by":"publisher","DOI":"10.1021\/jacsau.5c00947"},{"key":"2026082510251068000_2026.08.09.743796v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.celbio.2026.100452"},{"key":"2026082510251068000_2026.08.09.743796v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-025-02061-0"},{"key":"2026082510251068000_2026.08.09.743796v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2024.09.008"},{"key":"2026082510251068000_2026.08.09.743796v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60051-6"},{"key":"2026082510251068000_2026.08.09.743796v2.17","doi-asserted-by":"publisher","DOI":"10.1101\/2025.03.17.643752"},{"key":"2026082510251068000_2026.08.09.743796v2.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-024-01201-x"},{"key":"2026082510251068000_2026.08.09.743796v2.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.027"},{"key":"2026082510251068000_2026.08.09.743796v2.20","doi-asserted-by":"publisher","DOI":"10.1101\/2023.08.31.555663"},{"key":"2026082510251068000_2026.08.09.743796v2.21","doi-asserted-by":"publisher","DOI":"10.1101\/2025.09.23.678086"},{"key":"2026082510251068000_2026.08.09.743796v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/s42256-026-01237-5"},{"key":"2026082510251068000_2026.08.09.743796v2.23","doi-asserted-by":"publisher","DOI":"10.64898\/2026.01.12.699009"},{"key":"2026082510251068000_2026.08.09.743796v2.24","doi-asserted-by":"publisher","DOI":"10.1038\/s42256-025-01119-2"},{"key":"2026082510251068000_2026.08.09.743796v2.25","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btl158"},{"key":"2026082510251068000_2026.08.09.743796v2.26","doi-asserted-by":"publisher","DOI":"10.1021\/jo00165a018"},{"key":"2026082510251068000_2026.08.09.743796v2.27","doi-asserted-by":"publisher","DOI":"10.1021\/cr00032a005"},{"issue":"11","key":"2026082510251068000_2026.08.09.743796v2.28","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1021\/jp972949m","article-title":"Study of the polarity and hydrogen-bond ability of dodecyltrimethylammonium bromide micelles by the kamlettaft solvatochromic comparison method","volume":"102","year":"1998","journal-title":"The Journal of Physical Chemistry B"},{"key":"2026082510251068000_2026.08.09.743796v2.29","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2574"},{"issue":"2","key":"2026082510251068000_2026.08.09.743796v2.30","first-page":"3","article-title":"Lora: Low-rank adaptation of large language models","volume":"1","year":"2022","journal-title":"Iclr"},{"key":"2026082510251068000_2026.08.09.743796v2.31","doi-asserted-by":"publisher","DOI":"10.1021\/bi00699a002"},{"key":"2026082510251068000_2026.08.09.743796v2.32","doi-asserted-by":"crossref","unstructured":"Passaro, S. , Corso, G. , Wohlwend, J. , Reveiz, M. , Thaler, S. , Somnath, V.R. , Getz, N. , Portnoi, T. , Roy, J. , Stark, H. , et al.: Boltz-2: Towards accurate and efficient binding affinity prediction. BioRxiv (2025)","DOI":"10.1101\/2025.06.14.659707"},{"issue":"suppl 1","key":"2026082510251068000_2026.08.09.743796v2.33","first-page":"202","article-title":"Aaindex: amino acid index database, progress report 2008","volume":"36","year":"2007","journal-title":"Nucleic acids research"},{"key":"2026082510251068000_2026.08.09.743796v2.34","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-024-07487-W"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.08.09.743796","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:25:30Z","timestamp":1787678730000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.08.09.743796"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":34,"URL":"https:\/\/doi.org\/10.64898\/2026.08.09.743796","relation":{},"subject":[],"published":{"date-parts":[[2026,8,11]]},"subtype":"preprint"}}