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The disease correlates with the formation of insoluble aggregates mostly composed of patient-specific antibody light chains, whose hypervariable regions make each case unique and highlight the need for personalized therapeutics. In this study, we focused on a pathogenic homodimer we previously obtained from a patient-derived light chain. By analyzing the dynamics and the interface of this dimer, we identified a peptide with potential inhibitory activity. The peptide was then refined using a computational mutagenesis protocol that iteratively improved its sequence to maximize complementarity with the protein interface, taking into account shape, electrostatics, and hydropathy. The resulting optimized peptide is found to bind the monomer with a binding affinity comparable to that of the full pathogenic interface. These results suggest that the designed peptide could act as an effective antagonist of the pathogenic dimer, and demonstrate that our computational strategy could provide a general framework for designing patient-specific inhibitory peptides against aggregation-prone proteins.<\/jats:p>","DOI":"10.1021\/acs.jpcb.5c07238","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T11:19:52Z","timestamp":1775647192000},"page":"4259-4269","source":"Crossref","is-referenced-by-count":0,"title":["Preventing Pathogenic\nDimerization in a Misfolded\nAntibody Light Chain through the Design of an Inhibitory Peptide"],"prefix":"10.1021","volume":"130","author":[{"given":"Fausta","family":"Desantis","sequence":"first","affiliation":[{"name":"Istituto Italiano di Tecnologia (IIT), Center for Life Nano and Neuro Science , Viale Regina Elena 291 , ,","place":["Roma, Italy, 00161"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0043-8921","authenticated-orcid":true,"given":"Mattia","family":"Miotto","sequence":"additional","affiliation":[{"name":"Istituto Italiano di Tecnologia (IIT), Center for Life Nano and Neuro Science , Viale Regina Elena 291 , ,","place":["Roma, Italy, 00161"]},{"name":"Sapienza University of Rome , , Piazzale Aldo Moro, 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3046-5170","authenticated-orcid":true,"given":"Edoardo","family":"Milanetti","sequence":"additional","affiliation":[{"name":"Istituto Italiano di Tecnologia (IIT), Center for Life Nano and Neuro Science , Viale Regina Elena 291 , ,","place":["Roma, Italy, 00161"]},{"name":"Sapienza University of Rome , , Piazzale Aldo Moro, 5 , ,","place":["Rome, Italy, 00185"]},{"name":"Link Campus University , Via del Casale di San Pio V, 44 ,","place":["Rome, Italy, 00165"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Ruocco","sequence":"additional","affiliation":[{"name":"Istituto Italiano di Tecnologia (IIT), Center for Life Nano and Neuro Science , Viale Regina Elena 291 , ,","place":["Roma, Italy, 00161"]},{"name":"Sapienza University of Rome , , Piazzale Aldo Moro, 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4114-5049","authenticated-orcid":true,"given":"Lorenzo","family":"Di Rienzo","sequence":"additional","affiliation":[{"name":"Istituto Italiano di Tecnologia (IIT), Center for Life Nano and Neuro Science , Viale Regina Elena 291 , ,","place":["Roma, Italy, 00161"]},{"name":"Sapienza University of Rome , , P.le A. Moro 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"issue":"3","key":"2026090714122834900_cit1","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/nrd3050","article-title":"Protein aggregation diseases: pathogenicity and therapeutic\nperspectives","volume":"9","author":"Aguzzi","year":"2010","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"1","key":"2026090714122834900_cit2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0034-3","article-title":"Systemic immunoglobulin\nlight chain amyloidosis","volume":"4","author":"Merlini","year":"2018","journal-title":"Nat. Rev. Methods Primers"},{"issue":"1","key":"2026090714122834900_cit3","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1146\/annurev-biochem-061516-045049","article-title":"Propagation of protein\naggregation in neurodegenerative\ndiseases","volume":"88","author":"Vaquer-Alicea","year":"2019","journal-title":"Annu. Rev. Biochem."},{"issue":"1","key":"2026090714122834900_cit4","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1146\/annurev-biochem-061516-045115","article-title":"Protein misfolding,\namyloid formation, and human disease:\na summary of progress over the last decade","volume":"86","author":"Chiti","year":"2017","journal-title":"Annu. Rev. Biochem."},{"issue":"11","key":"2026090714122834900_cit5","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/nrd4593","article-title":"Targeting protein aggregation for\nthe treatment of degenerative diseases","volume":"14","author":"Eisele","year":"2015","journal-title":"Nat.\nRev. Drug Discovery"},{"issue":"6","key":"2026090714122834900_cit6","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1111\/febs.16390","article-title":"Antibodies\ngone bad\u2013the molecular mechanism of light chain amyloidosis","volume":"290","author":"Absmeier","year":"2023","journal-title":"FEBS J."},{"issue":"1","key":"2026090714122834900_cit7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26845-0","article-title":"Dissection of the amyloid\nformation pathway in al amyloidosis","volume":"12","author":"Kazman","year":"2021","journal-title":"Nat. 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Bioeng."},{"issue":"1","key":"2026090714122834900_cit50","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1002\/pro.3280","article-title":"Improvements\nto\nthe APBS biomolecular solvation software suite","volume":"27","author":"Jurrus","year":"2018","journal-title":"Protein Sci."}],"container-title":["The Journal of Physical\nChemistry B"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jpcb.5c07238","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/16\/4259\/68423051\/acs.jpcb.5c07238.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/16\/4259\/68423051\/acs.jpcb.5c07238.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T19:29:50Z","timestamp":1788809390000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article\/130\/16\/4259\/5150128\/Preventing-Pathogenic-Dimerization-in-a-Misfolded"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":50,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,4,8]]},"published-print":{"date-parts":[[2026,4,23]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jpcb.5c07238","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.09.16.676588","asserted-by":"object"}]},"ISSN":["1520-6106","1520-5207"],"issn-type":[{"value":"1520-6106","type":"print"},{"value":"1520-5207","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]}}}