The proposed research will develop an accessible, intuitive, and quantitative under- standing of proton-coupled electron transfer (PCET) processes. The primary focus is on processes in which a proton and an electron transfer in a single kinetic step but go to or come from distinct, separated sites. These multiple-site concerted proton-electron transfer (MS-CPET) reactions are widespread across biology but are not well understood. They are key to bioenergetics, central to the catalytic cycles of numerous metalloenzymes, and are involved in the chemistry of reactive oxygen species. MS-CPET is important in metabolism and bioactivation of many drugs, and defects in MS-CPET processes can lead to disease, for instance malfunctioning of the Q-cycle in complex III of the electron transport chain in mitochondria. The proposed studies will examine a range of small molecule systems to develop the fundamentals of MS-CPET and to model specific biochemical processes. The systems to be examined include phenols, iron porphyrins, ruthenium complexes, and models for iron/sulfur cluster cofactors. The phenol studies, for instance, will shed light on the formation of tyrosyl radicals in enzymatic catalysis or under oxidative stress. Using a broad range of model systems will provide insights that can be confidently transferred to more complex biological systems. Studies under specific aim 1 will build an intuition about these processes, for instance testing our hypothesis that separation of the electron and proton often does not inhibit the rate of reaction. Systematic variation of the e-/H+ separation and other relevant parameters will help develop quantitative models of how each parameter affects the MS-CPET reactions (specific aim 2). These studies will provide tests of current theory, and will explore how to simplify these theories to capture the larger effects and to be more accessible to experimentalists.
Specific aim 3 is to discover and understand the first examples of MS-CPET reactions involving C-H bonds, which could play an unappreciated role in biochemical processes. Together, the results from the different systems will build new intuition about MS-CPET and will provide the basis for new quantitative models. These will provide valuable understanding of a wide range of biological processes, and thus will be part of the foundation on which biomedical advances are built. The detailed knowledge available for electron transfer reactions has proven to be of great importance in biology. The work proposed aims to build a similarly valuable understanding for reactions that involve coupled transfers of electrons and protons.

Public Health Relevance

This project is developing a fundamental understanding of a class of chemical processes that occur widely in biology, the coupled transfers of electrons and protons. These chemical reactions are central to fields as diverse as bioenergetics and the action of antioxidants. Understanding these chemical processes is an important part of the foundation on which biomedical advances are being built.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
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Anderson, Vernon
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Porter, Thomas R; Mayer, James M (2014) Radical Reactivity of the Fe(III)/(II) Tetramesitylporphyrin Couple: Hydrogen Atom Transfer, Oxyl Radical Dissociation, and Catalytic Disproportionation of a Hydroxylamine. Chem Sci 5:372-380
Saouma, Caroline T; Pinney, Margaux M; Mayer, James M (2014) Electron transfer and proton-coupled electron transfer reactivity and self-exchange of synthetic [2Fe-2S] complexes: models for Rieske and mitoNEET clusters. Inorg Chem 53:3153-61
Saouma, Caroline T; Mayer, James M (2014) Do Spin State and Spin Density Affect Hydrogen Atom Transfer Reactivity? Chem Sci 5:
Albers, Antonia; Demeshko, Serhiy; Dechert, Sebastian et al. (2014) Fast proton-coupled electron transfer observed for a high-fidelity structural and functional [2Fe-2S] Rieske model. J Am Chem Soc 136:3946-54
Porter, Thomas R; Kaminsky, Werner; Mayer, James M (2014) Preparation, structural characterization, and thermochemistry of an isolable 4-arylphenoxyl radical. J Org Chem 79:9451-4
Saouma, Caroline T; Kaminsky, Werner; Mayer, James M (2013) Decomposition of a Mixed-Valence [2Fe-2S] Cluster to Linear Tetra-Ferric and Ferrous Clusters. Polyhedron 58:60-64
Warren, Jeffrey J; Menzeleev, Artur R; Kretchmer, Joshua S et al. (2013) Long Range Proton-Coupled Electron Transfer Reactions of Bis(imidazole) Iron Tetraphenylporphyrins Linked to Benzoates. J Phys Chem Lett 4:519-523
Saouma, Caroline T; Kaminsky, Werner; Mayer, James M (2012) Protonation and concerted proton-electron transfer reactivity of a bis-benzimidazolate ligated [2Fe-2S] model for Rieske clusters. J Am Chem Soc 134:7293-6
Mayer, James M (2011) Understanding hydrogen atom transfer: from bond strengths to Marcus theory. Acc Chem Res 44:36-46
Mayer, James M (2011) A Simple Marcus-Theory Type Model for Hydrogen Atom Transfer/Proton-Coupled Electron Transfer. J Phys Chem Lett 2:1481-1489

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