Molecular recognition of glycosaminoglycans and their sulfated deep-sea bacteria-derived mimetics, diabolican and...

Maintenance of bone function and remodelling is a strictly controlled physiological process that is modulated by bone forming and resorbing, mediated by osteoblasts and osteoclasts respectively. A signalling axis involved in controlling this process involves receptor activator of nuclear factor kappa B ligand, receptor activator of nuclear factor kappa B and osteoprotegerin. The two former proteins are vital in osteoclastogenesis whilst osteoprotegerin serves a modulatory role, interfering with the interaction of the other two proteins. The binding of these proteins by glycosaminoglycans has been identified, however the atomistic details are poorly understood. Here, computational simulations have been used to characterise the protein-glycosaminoglycan interactions within this signalling axis. Molecular docking calculations were carried out with glycosaminoglycan ligands and branched mimetics, diabolican and infernan derived from the deep-sea bacteria, to determine binding sites along with molecular dynamics and MM-GBSA to assess stability and determine the energetic preferences of the ligands. From these calculations, the binding sites in each protein-ligand pair have been identified along with details of how the ligand properties contribute to complex stability, overlap between these binding sites and the inter-protein interfaces has been demonstrated and electrostatics has also been identified as a primary driver of these interactions. These findings represent a key step towards understanding the interplay of signalling molecules in the regulation of osteoclastogenesis.