Foldamer-peptide conjugates as hydrogenase mimics

• Applicant: Professor Dr. Nils Metzler-Nolte
• Subject Area: Biological and Biomimetic Chemistry ; Inorganic Molecular Chemistry - Synthesis and Characterisation ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259117146

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.

• DFG Programme: Research Grants
• International Connection: France
• Participating Person: Dr. Yann Ferrand