Qiu S R, Wierzbicki A, Orme C A, Cody A M, Hoyer J R, Nancollas G H, Zepeda S, De Yoreo J J
Department of Chemistry and Materials Science, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94551, USA.
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1811-5. doi: 10.1073/pnas.0307900100. Epub 2004 Feb 6.
Calcium oxalate monohydrate (COM), which plays a functional role in plant physiology, is a source of chronic human disease, forming the major inorganic component of kidney stones. Understanding molecular mechanisms of biological control over COM crystallization is central to development of effective stone disease therapies and can help define general strategies for synthesizing biologically inspired materials. To date, research on COM modification by proteins and small molecules has not resolved the molecular-scale control mechanisms. Moreover, because proteins directing COM inhibition have been identified and sequenced, they provide a basis for general physiochemical investigations of biomineralization. Here, we report molecular-scale views of COM modulation by two urinary constituents, the protein osteopontin and citrate, a common therapeutic agent. Combining force microscopy with molecular modeling, we show that each controls growth habit and kinetics by pinning step motion on different faces through specific interactions in which both size and structure determine the effectiveness. Moreover, the results suggest potential for additive effects of simultaneous action by both modifiers to inhibit the overall growth of the crystal and demonstrate the utility of combining molecular imaging and modeling tools for understanding events underlying aberrant crystallization in disease.
一水合草酸钙（COM）在植物生理学中发挥着功能性作用，却是人类慢性疾病的一个源头，它构成了肾结石的主要无机成分。了解生物对COM结晶进行控制的分子机制是开发有效的结石疾病疗法的核心，并且有助于确定合成受生物启发材料的通用策略。迄今为止，关于蛋白质和小分子对COM修饰的研究尚未解析分子尺度的控制机制。此外，由于已鉴定并测序了指导COM抑制的蛋白质，它们为生物矿化的一般物理化学研究提供了基础。在此，我们报告了两种尿液成分——蛋白质骨桥蛋白和常见治疗剂柠檬酸盐对COM进行调节的分子尺度观点。通过将力显微镜与分子建模相结合，我们表明它们各自通过特定相互作用固定不同晶面上的台阶运动来控制生长习性和动力学，在这些相互作用中，尺寸和结构都决定了有效性。此外，结果表明两种修饰剂同时作用产生累加效应以抑制晶体整体生长的可能性，并证明了结合分子成像和建模工具对于理解疾病中异常结晶背后事件的实用性。
