Huhn A.Nissley D.Wilson D.B.Kutuzov M.A.Donat R.Tan T.K.Zhang Y.Barton M.I.Liu C.Dejnirattisai W.Supasa P.Mongkolsapaya J.Townsend A.James W.Screaton G.van der Merwe P.A.Deane C.M.Isaacson S.A.Dushek O.Mahidol University2025-01-232025-01-232025-12-01Nature Communications Vol.16 No.1 (2025)https://repository.li.mahidol.ac.th/handle/20.500.14594/102848Key functions of antibodies, such as viral neutralisation, depend on high-affinity binding. However, viral neutralisation poorly correlates with antigen affinity for reasons that have been unclear. Here, we use a new mechanistic model of bivalent binding to study >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces. The model provides the standard monovalent affinity/kinetics and new bivalent parameters, including the molecular reach: the maximum antigen separation enabling bivalent binding. We find large variations in these parameters across antibodies, including reach variations (22–46 nm) that exceed the physical antibody size (~15 nm). By using antigens of different physical sizes, we show that these large molecular reaches are the result of both the antibody and antigen sizes. Although viral neutralisation correlates poorly with affinity, a striking correlation is observed with molecular reach. Indeed, the molecular reach explains differences in neutralisation for antibodies binding with the same affinity to the same RBD-epitope. Thus, antibodies within an isotype class binding the same antigen can display differences in molecular reach, substantially modulating their binding and functional properties.ChemistryBiochemistry, Genetics and Molecular BiologyPhysics and AstronomyArticleSCOPUS10.1038/s41467-024-54916-52-s2.0-852140018812041172339746910