Coarse-Graining the Recognition of a Glycolipid by the C-Type Lectin Mincle Receptor

Macrophage inducible Ca²⁺-dependent lectin (Mincle) receptor recognizes <i>Mycobacterium tuberculosis</i> glycolipids to trigger an immune response. This host membrane receptor is thus a key player in the modulation of the immune response to infection by <i>M. tuberculosis</i> and has emerged as a promising target for the development of new vaccines against tuberculosis. The recent development of the Martini 3 force field for coarse-grained (CG) molecular modeling allows the study of interactions of soluble proteins with small ligands which was not typically modeled well with the previous Martini 2 model. Here, we present a refined approach detailing a protocol for modeling interactions between a glycolipid and its receptor at a CG level using the Martini 3 force field. Using this approach, we studied Mincle and identified critical parameters governing ligand recognition, such as loop flexibility and the regulation of hydrophobic groove formation by calcium ions. In addition, we assessed ligand affinity using free energy perturbation calculations. Our results offer mechanistic insight into the interactions between Mincle and glycolipids, providing a basis for the rational design of molecules targeting this type of membrane receptors.