# Coupled Transfers of Electrons and Protons

> **NIH NIH R35** · YALE UNIVERSITY · 2023 · $418,750

## Abstract

PROJECT SUMMARY/ABSTRACT
 The proposed research will develop a conceptual and quantitative framework for proton-coupled electron
transfer (PCET) processes, in which the proton and electron transfer in a single chemical step. Such reactions
are key to a wide range of essential biochemical processes, including respiration, photosynthesis and other
aspects of bioenergetics, catalysis in oxidoreductases and other metalloenzymes, and the behavior of reactive
oxygen species and antioxidants. These chemical reactions vary from hydrogen atom transfer (HAT), in which
the two particles move ‘together,’ to processes where the proton and electron move to (or come from) different
locations (multiple-site concerted proton-electron transfers, MS-CPET). Building on our prior studies and the
specific advances in the last period. this project will examine how the rates and selectivities of such reactions
are controlled by factors beyond the thermochemistry.
 Many biochemical processes interconvert carbon-centered radicals and C–H bonds, yet some of their
reactions have little if any precedent in standard organic chemistry. For example, isoergic and uphill H-transfer
between carbon atoms are extremely slow in solution, yet such reactions are widely used by the enzyme families
with radical-SAM and vitamin B-12 cofactors, often reversibly. There are few solution examples of MS-CPET
reactions of C–H bonds, yet these are predicted to be used in various enzymes in biology. Experiments using
both organic and transition metal model systems will probe the essential properties of these reactions. These
will include (i) shortening the H-transfer distance; (ii) polar effects; and/or (iii) having asynchronous transfer of
the electron and proton due to asymmetry of the reaction free energy surface. HAT and MS-CPET processes
may involve these factors in different ways.
 The oxidations of O–H bonds in biological systems often occur by MS-CPET, with proton transfer to a
hydrogen-bonded base coupled to long-distance electron transfer. Examples range from the tyrosine-histidine
pair in photosystem II to the multiple tyrosines in ribonucleotide reductases. Our recent studies of anthracene-
phenol-pyridine triads provide new approaches to disentangle the key parameters affecting these reactions, their
intrinsic barriers, vibronic couplings, and the nature of the hydrogen bonds. These systems undergo very rapid
photo-induced PCET, including the first example of PCET in the Marcus Inverted Region, and can be tuned with
various substitutions. This is an excellent platform to investigate the key parameters of MS-CPET in hydrogen-
bonded systems, which are common biochemical reactions.
 This project will construct a more comprehensive and quantitative understanding of the intrinsic properties
of PCET that are relevant to a range of important biochemical processes. These fundamental insights about
redox reactions of C–H and O–H bonds will help unravel how biology evolved to control difficul...

## Key facts

- **NIH application ID:** 10534742
- **Project number:** 5R35GM144105-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JAMES M MAYER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534742

## Citation

> US National Institutes of Health, RePORTER application 10534742, Coupled Transfers of Electrons and Protons (5R35GM144105-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10534742. Licensed CC0.

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