Foldamer-peptide conjugates as hydrogenase mimics

最近对能够产生二氢的酶[FeFe]-氢酶的研究表明，高速率的氢气产生需要在第二配位球上有特定的氨基酸残基。由于这种反应的价值，这种酶的合成模型比比皆是。然而，到目前为止，还没有模型复合体能够复制这种酶的高活性。将合成模型加入到旨在模拟第二配位球的支架上，可能会导致[FeFe]-H_2酶的仿生，其作用速度更接近酶。测试这一点的一个障碍是，以前使用的合成支架往往缺乏明确的结构或提供有限的官能团多样性。我们认为，用多肽片段功能化的芳香族寡酰胺折叠分子可以提供一个刚性的、定义良好的环境和高的合成模量性，从而可以在[FeFe]-H2酶模型周围合成定向的官能团阵列，甚至是酶相同的二配位球。在所提出的项目中，将围绕共价连接的仿生双铁模型络合物合成在溶液中具有特别稳定的二级结构的螺旋芳香族低聚酰胺锥。空腔的内壁将包含设计成模仿酶活性部位的官能团的官能团。此外，将使用点击化学作为提供更多样化功能的易变部位来添加基于小寡肽的末端基团。新混合体系的催化能力将通过电化学测试进行充分表征。此外，芳香族低聚酰胺的高晶体生长能力应该可以进行X射线结构表征。结合光谱研究，这些结果将为解释在电化学研究中观察到的变化提供基础。根据从这些试验中获得的数据，将开发一个反馈回路，以确定新的混合体系的结构/活性关系。通过使用这些结果，为了重新设计支架，将建立一个迭代过程，目标是不断提高对系统的理解和催化功能。正如这个项目将展示的那样，折叠酶和多肽的独特组合提供了一个新的、受生物启发的概念，有望彻底改变人工活性部位的设计。通过该项目为化学开辟了一个新的重大的长期前景：人工物体的从头合成在大小、复杂性和实现特定功能方面的效率方面类似于生物聚合物，但具有生物聚合物无法企及的化学结构。通过将这些设计扩展到生产模仿氢酶酶的第二配位球的催化剂，该项目旨在重新定义折叠器和人造催化剂设计的最新水平。

Recent studies on [FeFe]-Hydrogenase, an enzyme capable of producing dihydrogen, indicate that specific amino acid residues in the second coordination sphere are required for high rates of H2 production. Because of the value of this reaction, synthetic models of the enzyme abound. However, to date, no model complex has been able to replicate the high activity of the enzyme. Incorporation of a synthetic model onto a scaffold designed to mimic the second coordination sphere could lead to biomimetics of [FeFe]-H2ases that function at rates closer to the enzyme. One obstacle to testing this is that previously used synthetic scaffolds often lack a well-defined structure or offer limited functional group diversity. We propose that aromatic oligoamide foldamers functionalized with peptide segments can offer a solution by providing both a rigid, well-defined environment and high synthetic modularity, thus allowing the synthesis of oriented functional group arrays and even enzyme-identical second coordination spheres around models of [FeFe]-H2ase. For the proposed project, a helical aromatic oligoamide cone with a particularly stable secondary structures in solution will be synthesized around a covalently attached biomimetic diiron model complex. The interior walls of the cavity will incorporate functional groups designed to mimic those found in the enzyme active site. Additionally, a terminal group based on a small oligopeptide will be added using a click chemistry as a readily variable site for providing more diverse functionalities. The catalytic ability of the new hybrid systems will be fully characterized via electrochemical assays for hydrogen production. Additionally, the high crystal growth ability of aromatic oligoamides should allow X-ray structural characterization. Combined with spectroscopic studies these results will provide a basis for interpreting changes observed in the electrochemical studies. Based on the data obtained from these tests a feedback loop will be developed for determining a structure/activity relationship for the new hybrid systems. By using these results, to redesign the scaffold, an iterative process will be established with the goal being to continually improve both the understanding and the catalytic functionality of the system. As this project will demonstrate, the unique combination of foldamers and peptides offers a new, bio- inspired concept that promises to revolutionize the design of artificial active sites. Through this project a new major long term prospect is opened to chemistry: the de novo synthesis of artificial objects resembling biopolymers in terms of their size, complexity, and efficiency at achieving defined functions, yet having chemical structures beyond the reach of biopolymers. By extending these designs to produce catalysts that mimic the second coordination sphere of hydrogenase enzymes this project aims at redefining the state of the art both in foldamer and artificial catalyst design.