{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T06:21:52Z","timestamp":1772000512892,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Immun4Cure University Hospital Institute \u201cInstitute for innovative immunotherapies in autoimmune diseases\u201d","award":["2030\/ANR-23-IAHU-0009"],"award-info":[{"award-number":["2030\/ANR-23-IAHU-0009"]}]},{"DOI":"10.13039\/501100010190","name":"GENCI","doi-asserted-by":"crossref","award":["2023-AD010714493"],"award-info":[{"award-number":["2023-AD010714493"]}],"id":[{"id":"10.13039\/501100010190","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>Background\/Objectives: Antibody-dependent cellular cytotoxicity relies on the interaction between the Fc region of immunoglobulin G1 (IgG1) and the CD16a receptor. While removal of core fucosylation on Fc and introduction of the DFTE mutation set (S239D, H268F, S324T, I332E) are known to enhance CD16a binding, the detailed contributions of these engineered sites in solution remain incompletely defined. Methods: Here, we employed 1 \u00b5s molecular dynamics simulations to map, at atomic resolution, the interaction networks stabilizing pre-formed Fc-CD16a complexes, including afucosylated Fc-wild-type, DFTE-engineered, Fc-fucosylated, and asymmetrically engineered Fc variants. Results: Our results show that only S239D, present on both Fc chains, and H268F on chain A consistently contribute to stabilizing the CD16a interface, while I332E does not form persistent interactions. Glycan\u2013protein contacts are primarily intrachain, with transient interchain glycan\u2013glycan interactions not contributing significantly to complex stability. Fucosylation on Fc significantly reduces binding stability by disrupting peripheral interactions and critical glycan-mediated contacts. Notably, the asymmetric Fc variant, in which the two heavy chains carry distinct sets of substitutions, retains high-affinity binding despite lacking S239D and carrying core fucose, through a novel hydrophobic cluster and reinforced peripheral electrostatic interactions. Conclusions: Altogether, these findings provide a quantitative framework for how targeted mutations and fucose modifications remodel Fc-CD16a interactions, offering insights for the rational design of next-generation therapeutic antibodies.<\/jats:p>","DOI":"10.3390\/antib15010017","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T16:22:55Z","timestamp":1771863775000},"page":"17","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microsecond Dynamics of Fc\u2013CD16a Recognition: Impact of Mutations, Core Fucosylation, and Fc Asymmetry"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2901-5464","authenticated-orcid":false,"given":"S\u00e9bastien","family":"Estaran","sequence":"first","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron (IBMM), Universit\u00e9 de Montpellier, CNRS, \u00c9cole Nationale Sup\u00e9rieure de Chimie de Montpellier (ENSCM), 34090 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernard","family":"Hehlen","sequence":"additional","affiliation":[{"name":"Laboratoire Charles Coulomb, UMR 5221, CNRS, Universit\u00e9 de Montpellier, 34095 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0512-5115","authenticated-orcid":false,"given":"Alain","family":"Chavanieu","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron (IBMM), Universit\u00e9 de Montpellier, CNRS, \u00c9cole Nationale Sup\u00e9rieure de Chimie de Montpellier (ENSCM), 34090 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1749-6632.1971.tb13520.x","article-title":"ANTIBODY STRUCTURE AND MOLECULAR IMMUNOLOGY*","volume":"190","author":"Edelman","year":"1971","journal-title":"Ann. 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