{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:19:29Z","timestamp":1785435569474,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,1]]},"group-title":"Biophysics","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM151231-01"],"award-info":[{"award-number":["R35GM151231-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03g03ge92","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Core fucosylation of the IgG1 Fc N297 glycan is known to reduce binding affinity to the Fc\u03b3RIIIa (CD16a) receptor and attenuate antibody-dependent cellular cytotoxicity (ADCC), yet the structural mechanisms underlying this effect remain incompletely understood. Here, we use extensive all-atom molecular dynamics simulations to systematically investigate how Fc glycosylation modulates the structural, energetic, and dynamical landscape of the IgG1 Fc\u2013CD16a complex across multiple systems with fucosylation and galactosylation. Relative binding free energy calculations reproduce experimentally established trends, showing that afucosylation consistently strengthens Fc\u2013CD16a interactions. Mechanistically, dual fucosylation (on both Fc arms) increases inter-glycan packing between the Fc N297 glycans, restricts Fc glycan conformational sampling, and destabilizes the conformational organization of the CD16a N162 glycan. These glycan-mediated perturbations propagate to the protein interface. The result is reduced Fc\u2013CD16a contact persistence, redistribution of energetically important residues away from the canonical binding interface, and broader, less stable receptor-bound conformational states. Dynamic cross-correlation analysis further reveals that afucosylated systems maintain substantially stronger coordinated motions across the Fc\u2013CD16a assembly, whereas fucosylation disrupts long-range dynamic coupling between the receptor and antibody domains. Across these different energetic, structural, conformational, and dynamical readouts, fucosylation systematically shifts the Fc\u2013CD16a assembly from a compact, interface-stabilized binding mode toward a more heterogeneous and weakly coupled receptor-bound ensemble. Together, our findings set forth a mechanistic basis for Fc glycosylation regulating receptor engagement through ensemble-level conformational and dynamical reorganization rather than simple local steric effects. These results provide mechanistic design principles for rational Fc glycoengineering and the development of therapeutic antibodies with enhanced effector functions. More broadly, this work highlights how glycan composition can be leveraged as a tunable molecular design parameter for engineering protein recognition, conformational stability, and immune effector function in therapeutic glycoproteins.<\/jats:p>","DOI":"10.64898\/2026.06.26.732000","type":"posted-content","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T19:30:13Z","timestamp":1782934213000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular Basis of Core Fucosylation-Dependent Modulation of IgG1 Fc\u2013CD16a Binding"],"prefix":"10.64898","author":[{"given":"Natesan","family":"Mani","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alla","family":"Polozova","sequence":"additional","affiliation":[{"name":"Pivotal Attribute Sciences, Process Development, Amgen, Cambridge, MA 02141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7155-2764","authenticated-orcid":false,"given":"Srirupa","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Northeastern University, Boston, MA 02115"},{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115"},{"name":"Department of Physics, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070309100606000_2026.06.26.732000v1.1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1146\/annurev-bioeng-082721-024500","article-title":"Improving Antibody Therapeutics by Manipulating the Fc Domain: Immunological and Structural Considerations","volume":"24","year":"2022","journal-title":"Annu Rev Biomed Eng"},{"key":"2026070309100606000_2026.06.26.732000v1.2","doi-asserted-by":"crossref","unstructured":"Coenon, L. & Villalba, M . From CD16a Biology to Antibody-Dependent Cell-Mediated Cytotoxicity Improvement. Front Immunol 13, 913215 (2022).","DOI":"10.3389\/fimmu.2022.913215"},{"key":"2026070309100606000_2026.06.26.732000v1.3","doi-asserted-by":"crossref","unstructured":"Vidarsson, G. , Dekkers, G. & Rispens, T . IgG subclasses and allotypes: from structure to effector functions. Front Immunol 5, 520 (2014).","DOI":"10.3389\/fimmu.2014.00520"},{"key":"2026070309100606000_2026.06.26.732000v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s002770050396"},{"key":"2026070309100606000_2026.06.26.732000v1.5","doi-asserted-by":"crossref","unstructured":"X Li, T.P. , EE Brown and JC Edberg Fcg receptors: structure, function and role as genetic risk factors in SLE. 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