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Osteocalcin Facilitates Calcium Phosphate Ion Complex Growth as Revealed by Free Energy Calculation


The nanoscopic structural and thermodynamic basis of biomolecule-regulated assembly and crystallization of inorganic solids have tremendous impact on the rational design of novel functional nanomaterials, but are concealed by many difficulties in molecular-level characterization. Here we demonstrate that the free energy calculation approach, enabled by combining advanced molecular simulation techniques, can unravel the structural and energetic mechanisms of protein-mediated inorganic solid nucleation. It is observed that osteocalcin (OCN), an important non-collagenous protein involved in regulating bone formation, promotes the growth of nanosized calcium phosphate (CaP) ion clusters from supersaturated solution. Free energy calculation by umbrella sampling indicates that this effect by OCN is prominent at the scale of 1 to 3 nm ion-association complexes (IACs). The binding interactions between gamma-carboxyl glutamate and C-terminal and, interestingly, the arginine side chains of OCN with IACs stabilize under-coordinated IACs, thus promoting their growth. The promotor effect of OCN on the enlargement and further aggregation of IACs into cluster assemblies of 10s nm, are confirmed by conventional molecular dynamics simulation and dynamic light scattering experiment. To the best of our knowledge, this is the first time that the free energy landscape of the early stages of CaP nucleation is shown. The free energy change as a function of IAC size shares the feature of decreasing monotonically as shown previously for the calcium carbonate system. Therefore, the nucleation of both these two major biominerals apparently involves an initial phase of liquid-like ionic aggregates. The structural and thermodynamic information regarding OCN-CaP interactions amplify the current understanding of biomineralization mechanisms at the nanoscale, with general relevance to biomolecule-tuned fabrication of inorganic materials.

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Publication details

The article was received on 16 Feb 2018, accepted on 09 Apr 2018 and first published on 09 Apr 2018

Article type: Paper
DOI: 10.1039/C8CP01105B
Citation: Phys. Chem. Chem. Phys., 2018, Accepted Manuscript
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    Osteocalcin Facilitates Calcium Phosphate Ion Complex Growth as Revealed by Free Energy Calculation

    W. Zhao, Z. Wang, Z. Xu and N. Sahai, Phys. Chem. Chem. Phys., 2018, Accepted Manuscript , DOI: 10.1039/C8CP01105B

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