Mechanisms of Hydrogenase Function

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With support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professor Brian Dyer of Emory University will study how hydrogenase enzymes work to catalyze the interconversion of protons and hydrogen, thereby very efficiently producing molecular hydrogen, itself an important fuel. Indeed, this enzyme-catalyzed reaction is perhaps the most basic electron and proton transfer reaction relevant to molecular fuel production. In biological systems, this interconversion takes place with extraordinary rates and little energy loss. The hydrogenases will serve as ideal models for understanding the basic principles of efficient catalysis of multi-electron, multi-proton chemistry for generation of solar fuels. Storing solar energy in molecular fuels requires new catalysts that can efficiently perform chemistry that involves several electrons and protons to generate high-energy, chemical bonds. While the structures of hydrogenases are known, their mechanisms remain poorly understood. Also, the structure of the metal active sites in hydrogenases has been exactly reproduced in some synthetic model complexes but these complexes have failed as catalysts, which highlights the importance of the protein architecture that surrounds the active site of the hydrogenases. The results of this research on the hydrogenases can inform the design of better catalysts for making solar fuels. The research will provide an opportunity to broadly train students in an interdisciplinary setting, pursuing questions that are relevant to renewable energy science.A key challenge in studying hydrogenase enzymes lies in elucidating the mechanistic basis for the high catalytic efficiency of these oxidoreductases. There are both practical questions here, due to the difficulty of resolving the molecular processes for enzymes with kcat 1000 s-1, and conceptual questions, due to the complexity of the structures and dynamics that orchestrate the electron and proton transfer reactions. In this work, the Dyer research team will develop a general methodology for the study of fast electron and proton transfer reactions and a framework for understanding proton coupled electron transfer (PCET) in the oxidoreductases. The newly developed methods will be general and in principle could be applied to any catalytic redox reaction. The fundamental mechanistic questions to be answered for the hydrogenases are also relevant for the broader class of oxidoreductases, particularly for those enzymes that activate small and stable molecules, such as CO dehydrogenase and nitrogenase, which catalyze the multi-electron reduction of carbon dioxide and nitrogen, respectively. The research is expected to contribute to the elucidation of fundamental factors that control low-barrier proton and electron flow and provide a foundation for understanding PCET mechanisms in enzymes and in synthetic catalysts.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.