Rational Design of Artificial Hydrogenases

University Of Mississippi, University MS

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Abstract

PROJECT SUMMARY/ABSTRACT Hydrogenases are complex metalloenzymes that generate energy for certain organisms or balance cellular redox potentials by catalyzing the reversible interconversion between H2 oxidation and H+ reduction, respectively. Unraveling the intricate details of the function of these enzymes will significantly advance H2- based, carbon-neutral alternative energy production. However, the complexity of these enzymes due to the presence of multiple metallic cofactors, low production yield, and deactivation makes studying these enzymes challenging. Our goal is to design new biomolecular artificial hydrogenases (ArHs) as functional analogs of these complex metalloenzymes. De novo design and repurposing of native proteins are appealing and well-established approaches to creating active sites of complex metalloproteins within minimal protein scaffolds. Although the designed systems are less complex, they serve as water-soluble functional analogs of the native metalloenzymes and provide a functional view of the chemistry. Employing these approaches, we propose to pursue two Specific Aims describing the overall design principles and functional/mechanistic attributes of the ArHs inspired by the [NiFe] hydrogenases. The overall objectives of this proposal are: i) to design mononuclear, multinuclear, and heterometallic active sites within designed biomolecular scaffolds; ii) characterize the physical and catalytic properties of these ArHs; iii) determine the timescales of electron transfer; iv) tune the pKa of ligand and outline the role of ligand protonation states in H2 evolution; v) identify the metallated species responsible for noncooperative H2 production; and vi) elucidate how multimetallic sites influence the properties/reactivity, ultimately attaining a wholesome view of H-H bond formation. Our strong preliminary results presented here attest that our objectives are achievable. Collectively, the results from this proposed work will impact the fields of metalloprotein design, bioinorganic chemistry, and alternative energy research. A novel class of ArHs will emerge, which will provide functional vignettes into the working principles of H+ reduction related to the native enzymes. The lessons from this study will enable us to prepare biosynthetic catalysts with novel properties and functions in the future.