A comparative investigation of the mannose binding interface in DC-SIGN and MRC1 carbohydrate recognition domains with all-atom molecular dynamics simulations

Protein-carbohydrate interactions play a key role in numerous biological processes, including immune response, and glycan-based ligands that can target specific protein receptors on a cell surface represent promising candidates for therapeutics applications. For example, in retinoblastoma, the DC-SIGN mannose receptor (MR) is overexpressed on the surface of pathogenic cell and represents an interesting target for mannose-based ligands. At the same time, these ligands should not bind the MRC1 receptor, which is expressed by adjacent, healthy, retinal pigment epithelial cells. Therefore, the challenge remains to obtain a detailed picture of the recognition process between carbohydrates and proteins, in order to design effective and selective therapeutic compounds. In this work we used classical, all-atom Molecular Dynamics (MD) simulations to investigate the interaction between several mannose based ligands and the CRDs from DC-SIGN and MRC1. The analysis of the protein-carbohydrate contacts from the resulting trajectory highlights the variability of the mannose binding modes on both CRDs, and shows how the increased affinity of mannose for the MRC1 CRD can be related to a specific mannose binding state that is not accessible in the DC-SIGN CRD.