The fact that both DC-SIGN and DC-SIGN-C display the same binding mode and similar affinities in binding to QD-DiMan but with vastly different binding thermodynamic profiles suggests that, although the C-terminal segment does not directly define the CRD orientation in DC-SIGN, it still plays a key role in controlling DC-SIGN binding properties. Given that this segment is located at the flexible CRD/neck junction, it may act as a steric barrier to control the CRD flexibility, forcing each CRD to function an independent unit to retain specific MLGI. If this is the case then the CRDs in DC-SIGN-C would be less restricted and more able to change position relative to one another compared to that in DC-SIGN. This would inevitably lead to CRD-CRD and/or CRD-neck interactions upon QD-DiMan binding, which may account for the observed ∆𝐻 penalty. This steric influence of the C-terminal segment can also rationalize the enhancement of ∆𝑆 in DC-SIGN-C-QD-DiMan binding, whereby the new found flexibility of the CRDs would allow for the preservation of the flexibility of both the CRDs and flexible EG11 chains of the QD-DiMan scaffold. This binding interaction may even relieve some of the steric strain on each CRD, leading to the positive entropy term. This rationale would also agree with the entropic penalty observed in DC-SIGN, where a more rigid CRD arrangement would cause in a loss of the degrees of freedom in the EG11 chains, upon binding.