Xu Zhijun, Zhao Weilong, Wang Ziqiu, Yang Yang, Sahai Nita
State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, Nanjing 210009, China.
Phys Chem Chem Phys. 2018 Jan 17;20(3):1513-1523. doi: 10.1039/c7cp05261h.
Bone is a hierarchical biocomposite material in which a collagen fibril matrix self-assembled in a three-dimensional (3-D) pseudohexagonal array controls many important processes in mineralization such as providing the pathways by which calcium and phosphate species are delivered and a template for the earliest nucleation sites, determining the spatial distribution of the mineral and the topology for binding of associated non-collagenous proteins. However, the structural characteristics of collagen molecules in the fibril remain unclear at the atomic level. Here we performed the first large-scale molecular dynamics simulations to provide a comprehensive all-atom structural analysis of the entire fibril of Type I collagen including intra-fibrillar water distribution. We found that the ideal fibril structure is preserved in specific sites where the earliest nucleation occurs, but is severely distorted in areas that mineralize later. In detail, the ideal pseudohexagonal structure is well-preserved in the overlap zone (c1, c2 and b bands), in the a bands of the hole zone but is severely distorted at the hole/overlap transition (d and c3 bands). As a result, the expected uniform "channel," formed by connecting holes in adjacent unit cells along the b-axis, and having dimensions of 1.5 nm height along the a-axis and width of 40 nm along the c-axis is not formed. The expected uniform channel of 1.5 nm height is preserved only in the a bands in a narrow sub-channel region only 5.8 nm wide. At the hole/overlap transition, an irregular, tortuous sub-channel of widely varying dimensions (∼1.8-4.0 nm height × ∼3.0 nm width) is formed. The well-defined sub-channel in the a bands along with their preferred orientation of charged amino acid residues could facilitate faster molecular diffusion than the tortuous sub-channels and ionic interactions, thus providing the first nucleation sites. Intra-fibrillar water occupies nano-spaces and shows low density (∼0.7 g cm), which should promote dehydration of ion species. These results provide the first atomic-level understanding of the structure of the collagen fibril and the properties of the aqueous compartments within the fibril, which offer a physical, chemical and steric explanation for calcium phosphate infiltration paths and for the initiation of mineralization at the a band collagen fibril. The mechanism revealed here for the observed specificity of collagen biomineralization in bone formation ultimately contributes to the biochemical and biomechanical functions of the skeleton.
骨是一种分层生物复合材料，其中以三维（3-D）伪六边形阵列自组装的胶原纤维基质控制着矿化过程中的许多重要过程，例如提供钙和磷酸盐物种传递的途径以及最早成核位点的模板，确定矿物质的空间分布以及相关非胶原蛋白结合的拓扑结构。然而，纤维中胶原分子的结构特征在原子水平上仍不清楚。在此，我们进行了首次大规模分子动力学模拟，以对I型胶原的整个纤维进行全面的全原子结构分析，包括纤维内水的分布。我们发现，理想的纤维结构在最早发生成核的特定部位得以保留，但在后期矿化的区域则严重扭曲。具体而言，理想的伪六边形结构在重叠区（c1、c2和b带）、孔区的a带中保存完好，但在孔/重叠过渡区（d和c3带）严重扭曲。结果，沿b轴连接相邻晶胞中的孔形成的预期均匀“通道”未形成，该通道沿a轴高度为1.5 nm，沿c轴宽度为40 nm。预期的1.5 nm高度的均匀通道仅在仅5.8 nm宽的狭窄子通道区域的a带中保留。在孔/重叠过渡处，形成了尺寸变化很大的不规则曲折子通道（高度约1.8 - 4.0 nm×宽度约3.0 nm）。a带中明确的子通道及其带电氨基酸残基的优先取向可能比曲折的子通道和离子相互作用促进更快的分子扩散，从而提供最早的成核位点。纤维内的水占据纳米空间并显示出低密度（约0.7 g/cm³），这应促进离子物种的脱水。这些结果首次提供了对胶原纤维结构以及纤维内水相区室性质的原子水平理解，为磷酸钙渗透路径以及a带胶原纤维矿化的起始提供了物理、化学和空间解释。此处揭示的骨形成中胶原生物矿化所观察到的特异性机制最终有助于骨骼的生化和生物力学功能。
