Modulating Radical Propagation in Proteins by Proton-Coupled Electron Transfer and Hydrogen Bonding.
- 1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York14853, United States.
- 2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York14853, United States.
Abstract
Long-range protein electron transfer (ET) often depends on tryptophan and tyrosine residues acting as radical relay sites. For example, cytochrome c peroxidase (CcP) generates a W191•+ radical to increase ET from cytochrome c (Cc) to the active center. W191 substitution to Tyr reduces ET rates, but introduction of an adjacent general base (as Glu or His) at position 232 (Y191:E/H232 CcP) recovers activity. E232 fluorination lowers the pKa of the conjugate base and confirms that a hydrogen bond is critical to elevate the Y191• formal potential for effective ET. Photoinitiated ET between Zn-porphyrin (ZnP) CcP (ZnCcP) and Cc also depends on activating Y191 with a basic residue but through a different mechanism than for the peroxide-driven system. In ZnCcP, pH dependencies and solvent isotope effects indicate that proton-coupled electron transfer to the basic residue and ZnP•+, respectively, facilitates Y191• formation. Replacing Cc with the irreversible oxidant [Co(NH3)5Cl]2+ isolates distinct protein radicals for characterization by electron paramagnetic resonance (EPR) spectroscopy. Radical distributions and computation indicate that W191•+ lies close in potential to ZnP•+ and that the two radicals exchange on a slow time scale despite their close separation. Remarkably, Y191:E/H232 ZnCcP variants propagate radicals differently to peripheral sites depending on the nature of the 232 residue. QM/MM calculations support radical exchange between ZnP•+/Trp•+ and the importance of a hydrogen bond to Y191• for maintaining a high potential to oxidize peripheral donors. These resolved reactivity patterns of CcP/ZnCcP have general relevance for engineering proton management to separate and migrate charge in proteins and potentially other molecular systems.
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BibTeX
@article{zawistowski2026modulating,
title = {{Modulating Radical Propagation in Proteins by Proton-Coupled Electron Transfer and Hydrogen Bonding.}},
author = {Rebecca K Zawistowski and Timothée Chauviré and Sutanuka Manna and Nandini Ananth and Brian R Crane},
journal = {Biochemistry},
year = {2026},
month = oct,
doi = {10.1021/acs.biochem.6c00525},
url = {https://europepmc.org/article/MED/42899587},
note = {CC BY},
}
RIS
TY - JOUR
TI - Modulating Radical Propagation in Proteins by Proton-Coupled Electron Transfer and Hydrogen Bonding.
AU - Rebecca K Zawistowski
AU - Timothée Chauviré
AU - Sutanuka Manna
AU - Nandini Ananth
AU - Brian R Crane
PY - 2026
DA - 2026/10/01
JO - Biochemistry
DO - 10.1021/acs.biochem.6c00525
UR - https://europepmc.org/article/MED/42899587
AB - Long-range protein electron transfer (ET) often depends on tryptophan and tyrosine residues acting as radical relay sites. For example, cytochrome c peroxidase (CcP) generates a W191•+ radical to increase ET from cytochrome c (Cc) to the active center. W191 substitution to Tyr reduces ET rates, but introduction of an adjacent general base (as Glu or His) at position 232 (Y191:E/H232 CcP) recovers activity. E232 fluorination lowers the pKa of the conjugate base and confirms that a hydrogen bond is critical to elevate the Y191• formal potential for effective ET. Photoinitiated ET between Zn-porphyrin (ZnP) CcP (ZnCcP) and Cc also depends on activating Y191 with a basic residue but through a different mechanism than for the peroxide-driven system. In ZnCcP, pH dependencies and solvent isotope effects indicate that proton-coupled electron transfer to the basic residue and ZnP•+, respectively, facilitates Y191• formation. Replacing Cc with the irreversible oxidant [Co(NH3)5Cl]2+ isolates distinct protein radicals for characterization by electron paramagnetic resonance (EPR) spectroscopy. Radical distributions and computation indicate that W191•+ lies close in potential to ZnP•+ and that the two radicals exchange on a slow time scale despite their close separation. Remarkably, Y191:E/H232 ZnCcP variants propagate radicals differently to peripheral sites depending on the nature of the 232 residue. QM/MM calculations support radical exchange between ZnP•+/Trp•+ and the importance of a hydrogen bond to Y191• for maintaining a high potential to oxidize peripheral donors. These resolved reactivity patterns of CcP/ZnCcP have general relevance for engineering proton management to separate and migrate charge in proteins and potentially other molecular systems.
SN - 0006-2960
SN - 1520-4995
ER -