<p>The Carbohydrate Recognition Domain (CRD) of immune system’s c-type lectin receptors (CLRs) preferentially interacts with the Capsular Polysaccharides (CPS) units. Implicit Ca²⁺ ions are crucial to CRD function. Increment of the ionic concentration explicitly affects the CPS recognition by CRD many-fold. DC-SIGN is one such CLR that acts for the differential recognition of the microbial CPS. The CPS mannotriose had the lowest binding energy (ΔG -4.7&#xa0;kcal/mol) and the maximum affinity for DC-SIGN with implicit Ca²⁺ ion. In the present investigation the ligand affinity increases with the rise of Ca²⁺ concentration up to 1.5&#xa0;M. Again, within the CRD the residues viz; Glutamate (347), Proline (348), and Asparagine (349) (EPN) were reported previously as essential for CPS unit coordination. Our analysis demonstrated that besides the EPN residues, CPS unit interacts with the neighboring Asparagine (350), Glutamate (354) and Asparagine (355) residues. Thus, these residues were replaced one at a time with Alanine (a charge neutral residue) to test their effect on the contact event. The CRD loses its affinity for recognition on the N350A, E354A, and D355A substitutions. Thus, this heterogeneity of CRD recognition towards Carbohydrate provides fresh information about the immune system’s theragnostic function. This new understanding of Ca²⁺-induced recognition may help design new theragnostic applications that boost our immune defenses against pathogenic evasion.</p>