Coarse-Graining\nthe Recognition of a Glycolipid by\nthe C‑Type Lectin Mincle Receptor

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