{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York14853, United States.",
    "Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York14853, United States."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Rebecca K Zawistowski"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Timothée Chauviré",
      "orcid": "0000-0002-9466-4785"
    },
    {
      "affs": [
        0
      ],
      "name": "Sutanuka Manna"
    },
    {
      "affs": [
        0
      ],
      "name": "Nandini Ananth",
      "orcid": "0000-0001-5845-1961"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Brian R Crane",
      "orcid": "0000-0001-8234-9991"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fp6p68pke0bnh.bib",
  "cited_by": 0,
  "doi": "10.1021/acs.biochem.6c00525",
  "fulltext_url": "https://europepmc.org/articles/PMC13689830",
  "id": "fp6p68pke0bnh",
  "issns": [
    "0006-2960",
    "1520-4995"
  ],
  "landing_url": "https://europepmc.org/article/MED/42899587",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1604|Metal-Catalyzed Oxygenation Mechanisms"
    ]
  ],
  "openalex": "W7214637063",
  "pdf_url": "https://europepmc.org/articles/PMC13689830?pdf=render",
  "pmcid": "PMC13689830",
  "pmid": "42899587",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/fp6p68pke0bnh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:37Z",
      "native_id": "MED:42899587",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42899587"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1604|Metal-Catalyzed Oxygenation Mechanisms",
      "subfield": "inorganic"
    }
  ],
  "title": "Modulating Radical Propagation in Proteins by Proton-Coupled Electron Transfer and Hydrogen Bonding.",
  "title_text": "Modulating Radical Propagation in Proteins by Proton-Coupled Electron Transfer and Hydrogen Bonding.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:37Z",
  "url": "https://research.draconitic.com/paper/fp6p68pke0bnh",
  "venue": "Biochemistry",
  "versions": []
}