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However, the molecular mechanism driving this effect has remained unclear. In this study, a combination of total internal reflection fluorescence (TIRF) microscopy, F\u00f6rster resonance energy transfer (FRET), nuclear magnetic resonance (NMR), and molecular dynamic simulation (MD) revealed that the double cooperative effect arises from the dynamic assembly and disassembly of LL\u201037\/HNP1 aggregates, where the degree of aggregation governs membrane toxicity and therefore influences the cell fate. The aggregation is driven primarily through hydrophobic interactions between several amino acids within LL\u201037 and HNP1. Interestingly, in membranes, this aggregation state is regulated by the lipid composition, where only anionic lipids can break up the aggregates and disperse peptides in the membranes, leading to the gain of peptides\u2019 function. Taking the advantage of the lipid composition difference, this enables the aggregates to destroy bacterial membranes, whereas protect eukaryotic cell membranes.<\/jats:p>","DOI":"10.1002\/anie.202516436","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T08:27:22Z","timestamp":1775118442000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aggregation\u2010State Dynamics Drive Double Cooperativity Between Antimicrobial Peptides LL\u201037 and HNP1"],"prefix":"10.1002","volume":"65","author":[{"given":"Yuge","family":"Hou","sequence":"first","affiliation":[{"name":"Institute of Industrial Science The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Industrial Science The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koh","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences The University of Tokyo  Bunkyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Higuchi","sequence":"additional","affiliation":[{"name":"New Industry Creation Hatchery Center Tohoku University  Sendai Miyagi Japan"},{"name":"Department of Physics, School of Science The University of Tokyo  Bunkyo\u2010Ku Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoshi","family":"Kaya","sequence":"additional","affiliation":[{"name":"Department of Physics, School of Science The University of Tokyo  Bunkyo\u2010Ku Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Pudong District Shanghai China"},{"name":"Medicinal Chemistry and Bioinformatics Center Shanghai JiaoTong University, School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Institute of Industrial Science The University of Tokyo  Tokyo Japan"},{"name":"Department of Materials Science and Engineering Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Industrial Science The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Data Science School of Frontier Engineering Kitasato University  Sagamihara\u2010shi Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3512-6036","authenticated-orcid":false,"given":"Kaori","family":"Sugihara","sequence":"additional","affiliation":[{"name":"Institute of Industrial Science The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(21)02724\u20100"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41563\u2010025\u201002164\u20103"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201017736\u2010x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13535"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau5480"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201021533\u20105"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssensors.0c02346"},{"key":"e_1_2_8_9_1","doi-asserted-by":"crossref","unstructured":"D.Gaspar A.Salom\u00e9 Veiga andM. 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