Biomimetic Models of "Acidic" Biomineralization Proteins

9513250埃文斯在生物矿化结构中，存在一组大分子，其主要功能是成核无机晶体并调节其生长。这些分子被称为“酸性”模板大分子。根据分子互补范式，有效的模板大分子必须将其配体原子组织成紧凑的阵列，以便该阵列与晶体基元上相应的金属原子阵列互补(Mann，1993)。问题是，模板大分子的这种“组织化”是如何实现的？在蛋白质模板大分子的情况下，如软体动物外壳、牙齿牙本质和骨骼中发现的酸性蛋白质，获得这种组织的问题成为蛋白质折叠的问题。因此，如果我们能够确定“酸性”蛋白质在二价阳离子和/或矿物晶体表面存在时如何折叠，我们就可以(1)了解这些复杂蛋白质是如何工作的，以及(2)最终将这些信息应用于无机基序识别聚合物的设计，这些聚合物可以用作新型复合材料制造中的组件。基于对“酸性”模板磷蛋白的开创性的核磁共振蛋白质折叠研究，我已经确定了“酸性”模板蛋白经历了pH和阳离子诱导的全局折叠转变，这些折叠转变是由铰链或中间结构域介导的，这些结构域两侧都有金属结合的聚电解质结构域。我推测，这种铰链介导的折叠过程可能代表了一种可能的机制，用于创建补充某些晶体基序的有组织的模板分子表面。在这份职业研究提案中，我将通过以下策略来完善我们对聚电解质-铰链折叠过程的知识：利用合成聚电解质-铰链-聚电解质(PHP)肽学、核磁共振波谱和分子模拟来探索铰链功能阳离子诱导的折叠过程。生物矿化组织，如骨、牙齿、海贝和浮游生物，代表着一种自然产生的复合材料：蛋白质和多糖与无机矿物晶体结合形成高度结构化、定义明确的材料，已存在数百万年。作为科学家，我们能从这些结构中了解到任何可能有助于我们寻找新的生物和生态兼容材料的知识吗？答案是肯定的，因为我们现在开始了解到，某些蛋白质可以通过特定的折叠途径与矿物结合，这反过来又可以在微观层面上影响矿物晶体的尺寸和大小。这项研究计划研究某些生物矿化蛋白质的氨基酸序列，并确定金属离子如何影响蛋白质的形状或“折叠”。我们的方法将包括核磁共振波谱和计算机模拟。这些信息将让我们了解蛋白质本身是如何调节矿物晶体大小的形成，最终是复合结构的形成。我的教学计划将强调师生计划，这将有助于改变纽约大学本科生和研究生的学习过程，并为高中生和小学生在大学期间需要发展的科学技能做好准备。***

9513250 Evans Within biomineralized structures, there exists a group of macromolecules whose primary function is the nucleation of inorganic crystals and the regulation of their growth. These molecules are referred to as "acidic" template macromolecules. According to the paradigm of molecular complementarity, an effective template macromolecule must organize its ligand atoms in a compact array, such that this array complements the corresponding metal atom array on a crystal motif (Mann, 1993). The question is, how is this "organization" of the template macromolecule achieved? In the case of protein template macromolecules, such as the "acidic" proteins found in mollusc shell, tooth dentine, and bone, the problem of attaining this organization becomes a problem in protein folding. Hence, if we can determine how "acidic" proteins fold in the presence of divalent cations and/or mineral crystal surfaces, we can (1) learn how these complex proteins work, and (2) eventually apply this information towards the design of inorganic motif-recognition polymers that can be utilized as components in the fabrication of novel composite materials. Based on pioneering NMR protein-folding studies of an "acidic" template phosphoprotein, phosphophoryn, I have determined that an "acidic" template protein undergoes pH- and cation-induced global folding transitions, and that these folding transitions are mediated by hinge or intervening domains that are flanked on either side by the metal-binding polyelectrolyte domains. I hypothesize that this hinge-mediated folding process may represent a possible mechanism for creating organized template molecular surfaces that will complement certain crystal motifs. In this CAREER research proposal, I will refine our knowledge of the polyelectrolyte-hinge folding process by using the following strategy: Explore hinge function the cation-induced folding process by utilizing synthetic polyelectrolyte-hinge-polyelectrolyte (PHP) peptidomimetics, NMR spectroscopy, and mo lecular modeling. %%% Biomineralized tissues, such as bone, teeth, sea shells, and plankton, represent a naturally-occuring composite material: Proteins and polysaccharides combine with inorganic mineral crystals to form highly structured, well-defined materials which have existed for millions of years. Can we, as scientists, learn anything about these structures that might help us in our quest for new bio- and eco-compatible materials? The answer is yes, since we are now beginning to understand that certain proteins can bind to minerals via a specific folding pathway, which, in turn, can affect the dimension and size of mineral crystals on a microscopic level. This proposal plans to study the amino acid sequences of certain biomineralization proteins, and, determine how metal ions affect the shape or "folding" of the protein. Our methods will include nuclear magnetic resonance spectroscopy and computer modeling. This information will give us some idea of how the proteins themselves regulate the formation of mineral crystal sizes, and ultimately, the formation of composite structures. My teaching proposal will emphasize teacher-student programs which will help to change the learning process at the undergraduate and graduate level at NYU, and, prepare high school and elementary school students for what science skills they will need to develop in their college years. ***