Osteocalcin facilitates calcium phosphate ion complex growth as revealed by free energy calculation
Osteocalcin facilitates calcium phosphate ion complex growth as revealed by free energy calculation
复制标题
自由能计算显示，骨钙素促进磷酸钙离子复合物的生长
DOI：
10.1039/c8cp01105b
复制
发表时间：
2018
影响因子：
3.3
通讯作者：
Sahai Nita
中科院分区：
文献类型：
--
作者：
Zhao Weilong;Wang Ziqiu;Xu Zhijun;Sahai Nita
生物分子调控的无机固体组装和结晶的纳米结构和热力学基础对新型功能纳米材料的合理设计具有巨大的影响，但被分子水平表征的许多困难所掩盖。在这里，我们证明了自由能计算方法，结合先进的分子模拟技术，可以解开蛋白质介导的无机固体成核的结构和能量机制。据观察，骨钙素（OCN），一个重要的非胶原蛋白参与调节骨形成，促进生长的纳米级磷酸钙（CaP）离子簇从过饱和溶液。伞式采样的自由能计算表明，OCN的这种影响是突出的1至3 nm的离子缔合复合物（IAC）的规模。γ-羧基谷氨酸和OCN和IAC的C-末端以及有趣的精氨酸侧链之间的结合相互作用稳定了配位不足的IAC，从而促进了它们的生长。通过分子动力学模拟和动态光散射实验证实了OCN对IACs的放大和进一步聚集成数十nm团簇的促进作用。据我们所知，这是第一次显示CaP成核早期阶段的自由能景观。作为IAC尺寸的函数的自由能变化共享如先前对于碳酸钙系统所示的单调减小的特征。因此，这两个主要的生物矿物的成核显然涉及液体样离子聚集体的初始阶段。关于OCN-CaP相互作用的结构和热力学信息放大了目前对纳米级生物矿化机制的理解，与生物分子调节的无机材料制造具有普遍相关性。
The nanoscopic structural and thermodynamic basis of biomolecule-regulated assembly and crystallization of inorganic solids have a 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 a 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 the C-terminal and, interestingly, the arginine side chains of OCN and IACs stabilize under-coordinated IACs, thus promoting their growth. The promoter effect of OCN on the enlargement and further aggregation of IACs into cluster assemblies of tens of nm are confirmed by conventional molecular dynamics simulation and dynamic light scattering experiments. 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 major biominerals apparently involves an initial phase of liquid-like ionic aggregates. The structural and thermodynamic information regarding OCN–CaP interactions amplifies the current understanding of biomineralization mechanisms at the nanoscale, with general relevance to biomolecule-tuned fabrication of inorganic materials.