Structural control of Fe(II)-based multivalent glycan assemblies enables intramolecular avidity and ultra-high-affinity binding

Abstract

Abstract Multivalent glycan recognition depends critically on the spatial organization of saccharides, yet quantitative design rules linking glycan geometry to binding remain poorly defined. Here, we report atomically-precise Fe(II)-based glycoassemblies that enable independent control of glycan valency, spacing, and topology within discrete molecular scaffolds. Using monomeric Griffithsin as a model lectin, we uncover that subtle changes in glycan presentation drive discrete transitions from partial site engagement to high-avidity, multi-site binding, spanning a > 10³-fold range in affinity. Structurally optimized assemblies achieve binding that surpass the binding strength of native high-mannose glycans, entering an effectively irreversible regime. These findings define geometric thresholds for intramolecular avidity and establish a framework for engineering multivalent ligands with programmable binding properties.