The theoretical maximum length at which the glycan ligands may be able to be compressed (𝑙) can be derived from the estimated length of flexibility in the glycan ligand, i.e. 𝑙 ~2.1 nm for DHLA-EG11-DiMan (see SI Section 7). Therefore, even with compression of the ligands, it would be impossible for all four binding sites to reach the glycan surface simultaneously. This means that the glycan displays at the QR ends are incapable of bridging all four binding sites in DC-SIGNR, thus the protein cannot access its most stable simultaneously bound state. Instead, it is forced to find its next most favorable configuration by crosslinking with other particles to maximize binding enthalpy. For the cylindrical section of the scaffold, the curvature of the round of the cylinder is the same as the spherical ends, however, along the length of the cylinder, it is roughly flat. This means that the tetrameric lectin has the opportunity to align itself with its longer length parallel to the length of the rod (Figure right). Therefore, only the short length of the tetramer (i.e. 𝑝 = 3.8 nm) needs to contribute to the separation distance (d) from the rod surface, resulting in a d of only ~0.4 nm. This is well within the maximum compression length of the ligands, therefore allowing glycans to easily bridge all 4 CRDs to give strong simultaneous tetravalent binding. Finally, the tetrameric model of DC-SIGN has been predicted to exhibit a more compact shape with an average diagonal inter-binding site distance of 5.6 nm (Figure ). This results in a much smaller separation distance between the protein contact area (𝑑 ≈ 1 nm), which is smaller than the maximum compression length of the flexible surface ligands (𝑙 = 2.1 nm). This would therefore easily allow the QR surface glycans to bridge all 4 CRDs, regardless of the region of the QR that DC-SIGN binds to, leading to the exclusively simultaneous binding mode as observed here. These calculations therefore show that while the tetrameric structures of both lectins are still unknown, the good agreement between the predicted and observed results suggests that the structural models for DC-SIGN/R are likely to be relatively reliable. Moreover, it also demonstrates that, by taking into account nano-scaffold curvature, estimating the 𝑑-𝑙 relationship between the protein and nano-scaffold dimensions can provide a useful prediction of the binding mode for multimeric lectins.