Foldamer-peptide conjugates as hydrogenase mimics

最近的研究[FeFe]-氢化酶，能够产生二氢的酶，表明，特定的氨基酸残基在第二个协调领域所需的高速率的H2生产。由于这种反应的价值，这种酶的合成模型比比皆是。然而，迄今为止，没有模型复合物能够复制酶的高活性。将合成模型结合到旨在模拟第二配位球的支架上可能会导致[FeFe]-H2酶的仿生学，其功能速率更接近酶。测试这一点的一个障碍是，以前使用的合成支架通常缺乏明确的结构或提供有限的官能团多样性。我们建议，芳香族低聚酰胺折叠体功能化肽段可以提供一个解决方案，提供一个刚性的，明确的环境和高合成模块化，从而允许定向功能组阵列的合成，甚至酶相同的第二协调领域周围的模型[FeFe]-H2 ase。对于拟议的项目，将围绕共价连接的仿生二铁模型复合物合成一种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。腔的内壁将结合设计成模拟酶活性位点中发现的那些官能团的官能团。此外，将使用点击化学添加基于小寡肽的末端基团作为容易可变的位点，以提供更多样化的功能。新的混合动力系统的催化能力将通过电化学测定制氢充分表征。此外，芳香族低聚酰胺的高晶体生长能力应允许X射线结构表征。结合光谱研究，这些结果将为解释电化学研究中观察到的变化提供基础。基于从这些测试中获得的数据，将开发用于确定新的混合系统的结构/活性关系的反馈回路。通过使用这些结果，重新设计支架，将建立一个迭代过程，目标是不断提高系统的理解和催化功能。正如这个项目将展示的那样，折叠体和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位点的设计。通过这个项目，一个新的主要的长期前景是打开化学：从头合成的人造物体类似于生物聚合物在其大小，复杂性和效率方面，在实现定义的功能，但具有超出生物聚合物的化学结构。通过扩展这些设计来产生模拟氢化酶的第二配位域的催化剂，该项目旨在重新定义折叠体和人工催化剂设计的最新技术水平。

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.