(194i) Mechanism of Osteocalcin Interactions with Hydroxyapatite Surfaces and Hydrogen Phosphate Precursors for Bone Mineralization

The mechanism of apatite mineralization mediated by osteocalcin, one of the non-collagenous proteins in bone and dentin, has only been marginally explored due to limitations in experimental imaging and spectroscopy techniques. Recent developments of computational models in the Interface force field (IFF) allow the precise atomically resolved study of the interaction of proteins with hydroxyapatite (HAp) and related minerals using molecular dynamics simulations, including accurate representations of chemical bonding and aqueous interfacial properties as a function of pH value. First, the interaction of osteocalcin with different (hkl) surfaces of HAp facets at pH values of 5, 7 and 10 is discussed and binding residues are identified. In contrast to the proposed role of the three surface-bound calcium ions of the protein as binding sites to hydroxyapatite, these surface-bound ions on the protein are not preferred interaction sites with the Hap surface. Instead, desorbed phosphate ions from the HAp surface, or other hydrogenphosphate precursor molecules in solution, coordinate with the three-calcium site of the protein. Therefore, it appears possible that this site of the protein assumes a prominent role in osteocalcin-mediated biomineralization. The results from molecular dynamics simulation strongly suggest that the three-calcium site of the protein acts as a nucleation site for apatite biomineralization. The hypothesis is in agreement with the prior findings on the proportionality between the number of bone grains and the amount of osteocalcin protein in blood. Revealing the role of osteocalcin in the biomineralization at the atomically resolved level is a significant step towards understanding the process of the bone mineralization, and illustrates the predictive capabilities of simulations using reliable force fields and surface model databases.