Tyrosine Mediated Proton-Coupled Electron Transfer Reactions
Date of Award
Doctor of Philosophy (PhD)
Molecular Biophysics and Biochemistry
Tyrosine residues can be redox active and play a role in enzymes such as photosystem II, cytochrome c oxidase, and ribonucleotide reductase. The large size of these enzymes and high potentials needed to oxidize tyrosine prohibits extensive experimental characterization of tyrosine redox potentials in their native protein environment. Tyrosine oxidation at typical biological pH is coupled to proton-transfer and thus proceeds via a proton-coupled electron transfer (PCET) reaction to form a neutral tyrosine radical. Radical intermediates can be transient and reactive and thus difficult to isolate. This precludes understanding the role of the solvated protein environment and electronic effects on tyrosine mediated PCET reactions. My dissertation studies these effects in a designed protein scaffold, alpha3X, which is a small helical bundle with a single tyrosine or fluorinated tyrosine analog residue buried in the interior. In conjunction with the lessons learned about PCET involving single electron and single proton transfers, I also examined a larger enzyme system, E. coli class Ia ribonucleotide reductase (RNR), which involves coupled PCET reactions involving predominantly tyrosine residues. This pathway of PCET reactions span over 32 Å, crossing a protein interface. I use molecular dynamics, electronic structure calculations, kinetic modeling and other techniques in computational chemistry to examine the thermodynamics, kinetics, and conformational changes that underlie tyrosine redox reactions.
Reinhardt, Clorice Rose, "Tyrosine Mediated Proton-Coupled Electron Transfer Reactions" (2022). Yale Graduate School of Arts and Sciences Dissertations. 515.