羟基磷灰石结晶路径上的中间体结构形成及相变机制的分子模拟研究

As an inorganic-organic composite with hierarchical origination, bone exhibits excellent chemical, biological and mechanical properties. The investigation on the crystallization pathway of hydroxyapatite, lies in the core of understanding bone mineralization mechanism, which will provide biomimetic mineralization approaches for material preparation. In this project, multiple intermediates (ions – prenucleation cluster – amorphous phase – crystal) involved in the crystallization pathway of hydroxyapatite will be systemically studied by exploring their equilibrium structures and thermodynamic behaviors, through an integrated approach combining classical molecular simulation and quantum mechanics. It is proposed that structural transformation between the different intermediates could be characterized by the free energy landscapes, through which the connection of the intermediate behaviors to the free energy change will be clarified. The simulation models of hydration amorphous calcium phosphate (ACP) with different proportions of water molecules will be built to investigate the role of dehydration and densification in dominating the ability of calcium/phosphate ion diffusion and surface migration. By employing the advanced sampling techniques, a series of intermediate states connecting ACP and hydroxyapatite are explored, and the free energy landscapes related to this process will offer an energetics way for quantitatively evaluating the existing mechanisms of ACP phase transformation and determining the favorable pathway. This project will deep the understanding on the biomineralization mechanism and benefit the design and application of new biomimetic materials.

骨骼是一种具有多级有序结构的有机-无机复合材料，拥有优异的化学、生物和力学性能。理解骨骼矿化机制以及实现其仿生材料制备，需要开展针对羟基磷灰石结晶机制的基础研究。本课题提出羟基磷灰石结晶过程描述：离子-预成核束-无定型前驱体-晶体，采用经典分子模拟和量子化学计算相结合的方法，研究水溶液中羟基磷灰石结晶过程中所涉及到的中间体平衡结构和动力学行为，提出以热力学自由能表征中间体结构改变方向和程度，建立自由能与中间体行为的构效关联。通过构筑不同水比重的水合无定型磷酸钙结构模型，研究其脱水和致密固化行为对离子动态扩散和表面迁移能力的控制规律。课题基于加强取样技术，模拟连接无定型前驱体和晶体结构之间的一系列中间体结构演化过程，并基于自由能计算对现有无定型磷酸钙转化机制提供能量学上的评价依据，确定最有利相变路径。研究结果将有助于深化理解生物矿化机制，同时对新型仿生材料的设计和制备有着重要指导意义。

本项目着重基于分子模拟手段，从微观水平上研究羟基磷灰石晶体结晶过程中水溶液相离子在不同阶段的聚集结构及相转化机理，细致考察离子之间的相互作用和溶剂化效应。项目基于统计力学理论，建立和发展了复杂自由能模拟计算方法，为探索水溶液中晶体成核和生长机制提供了可靠的理论模拟研究方法。利用增强采样技术，针对羟基磷灰石成核过程中涉及到的多种中间态，基于成核路径自由能的分步精确计算，探究了磷酸钙成核团聚体的形成和演变路径，阐明了溶液相成核过程中预成核团聚物中间态的形成及其稳定性，从能量学和微观水平上揭示了预成核束形成机理。通过自由能及其熵焓贡献的分解，研究了水分子介导的离子结合过程的热力学调控机制,揭示了熵驱动离子缔合过程的控制规律。项目采用特殊的模拟手段，在分子水平上研究了无定形磷酸钙结构（Amorphous Calcium Phosphate, ACP）的相转化机制，揭示了水分子通过与ACP表面磷酸根离子氢键的形成或断裂以完成界面迁移和释放的分子机制；通过对受限空间中晶体成核的模拟，揭示了水密度和受限空间尺寸对磷酸钙成核的影响规律，为胶原蛋白纤维受限空间内成核过程提供了数据支撑和理论解释。研究结果将有助于深化理解生物矿化过程及机制，为基于无定型前驱体制备精巧复杂的仿生材料提供理论指导。