Proton-Coupled Electron Transfer

Proton motion coupled to electron transfer is the basic mechanism of bioenergetic conversion. Small-molecule activation, redox-driven proton pumps, and radical initiation and transport of a wide variety of oxidases and reductases all involve the coupling of electrons to protons. However the mechanistic details of how the electron and proton couple remain largely unresolved. Our group seeks to define PCET mechanism on three fronts: (1) model systems, (2) biological enzymes utilizing amino acid radicals, and (3) catalysis.



The need to account for the effect of proton motion on ET in the PCET problem requires the development of new methods in chemistry and biology. We have synthetically designed donor/acceptor model systems with well-defined electron transfer distances and proton hydrogen bond geometries. PCET is initiated by laser excitation of the donor or the acceptor and the reaction is monitored by a wide array of ultrafast and nanosecond spectroscopies. Model systems studied to date have distinguished two types of PCET reactivity: co-linear PCET in which the electron and proton are transferred along the same vectorial coordinate and orthogonal PCET in which the electron and proton are transferred to disparate acceptors.

Owing to the mass difference between proton and electron, the electron can tunnel over long distances (tens of Å) while proton transfer is limited to a few Å. Kinetics studies to date have shown us that the proton location within the hydrogen bond plays a crucial role in charge separation, yet the precise timing of the proton to the electron in the PCET event has yet to be achieved. A major goal of our current research is to develop methods to monitor the fate of the proton in response to the electron and vice versa.



The PCET mechanisms of biological systems are a study focus in our group, with particular emphasis on enzymes utilizing amino acid radicals as redox active cofactors and charge transfer intermediates. As a case study, a collaborative effort between our group and the Stubbe group seeks to define the PCET reactivity of ribonucleotide reductase (RNR), which converts ribonucleotides to deoxyribonucleotides necessary for DNA synthesis through a radical-dependent mechanism. RNR is composed of two subunits: R1 contains the enzyme active site and R2 contains the assembled diiron-tyrosyl radical cofactor. For each turnover, the radical in R2 must transiently oxidize an active site cysteine residue in R1 located more than 35 Å away. Direct charge transport over such a long distance is unprecedented in chemistry and biology. Radical transport is proposed to occur via a PCET radical hopping pathway utilizing several conserved residues in R2 and R1 as radical intermediates.

To date, we have focused on elucidating the PCET mechanism for these radical hops, along with direct detection of the radical intermediates within RNR. Our current model for radical transport is depicted above. Within R2, long distance electron transport is coupled to short distance, orthogonal proton transfer within hydrogen bonds, while in R1 radical hopping appears to occur along a co-linear PCET pathway.



The mechanistic insights acquired from PCET studies in model and natural systems provide a roadmap to develop new platforms for catalytically activating small molecule substrates by PCET. Reactions of interest include oxidation of water to oxygen (Photosystem II) and reduction of protons to hydrogen (hydrogenase) for energy storage, along with the biologically relevant disproportionation of hydrogen peroxide (catalase) and oxidation of organic substrates with oxygen in cytochrome P450-type reactivity. In biology, nature has designed active sites for these reactions which utilize the acid/base functionality of the protein amino acid side chains in the secondary coordination sphere for substrate delivery to and assembly at the metallo-cofactor. To mimic this, we have designed novel “Hangman” platforms (porphyrins, shown below, and salens) with well-defined molecular clefts that combine both acid/base and redox functionalities.

These systems have found success in mimicking both catalase and peroxidase type reactivity. Studies with other oxidase- and hydrogenase-type catalysts are currently underway, including those that mimic the chemistry of the Oxygen Evolving Complex of Photosystem II. The “Hangman” acid/base functionality serves several purposes: (1) as a hydrogen bond scaffold for assembly of substrate, (2) as an intramolecular proton donor/acceptor to provide kinetic enhancement when diffusion of H+/base to the catalyst is rate-limiting, and (3) to provide hydrogen bonds to the substrate that can lower the activation energy for bond-making/-breaking reactions. These attributes result in enhanced catalytic activity by PCET.



REFERENCES

  1. "Re(bpy)(CO)3CN as a Probe of Conformational Flexibility in a Photochemical Ribonucleotide Reductase"; Steven Y. Reece, Mohammad R. Seyedsayamdost, JoAnne Stubbe and Daniel G. Nocera, Biochemistry 2007, submitted for publication.

  2. "Tipping Point Between Ionized Versus Non-Ionized Proton-Coupled Electron Transfer Interfaces"; Elizabeth R. Young, Joel Rosenthal and Daniel G. Nocera, Chem. Commun. 2007, submitted for publication.

  3. "Proton-Coupled Electron Transfer: The Engine that Drives Radical Transport and Catalysis in Biology"; Steven Y. Reece and Daniel G. Nocera in Quantum Tunneling in Enzyme Catalyzed Reactions; Nigel Scrutton and Rudolph Allenman, Eds.; Royal Society of Chemistry Press: London, 2007.

  4. "Proton-Coupled Electron Transfer of Tyrosine Oxidation: Buffer Dependence and Parallel Mechanisms"; Tania Irebo, Steven Y. Reece, Martin Sjödin, Daniel G. Nocera and Leif Hammarström, J. Am. Chem. Soc. 2007, ASAP Article; DOI: 10.1021/ja073012u.

  5. "Oxygen Activation Chemistry of Pacman and Hangman Porphyrin Architectures Based on Xanthene and Dibenzofuran Spacers"; Joel Rosenthal and Daniel G. Nocera, Prog. Inorg. Chem. 2007, 55, 483-544.

  6. "Direct Observation of a Transient Tyrosine Radical Competent for Initiating Turnover in a Photochemical Ribonucleotide Reductase"; Joel Rosenthal and Daniel G. Nocera, J. Am. Chem. Soc. 2007, 129, 13828-30.

  7. "The Role of Proton-Coupled Electron Transfer in O-O bond Activation"; Joel Rosenthal and Daniel G. Nocera, Acc. Chem. Res. 2007, 40, 543-53.

  8. "Structurally Homologous b- and meso-Alkynyl Amidinium Porphyrins"; Joel Rosenthal, Elizabeth R. Young and Daniel G. Nocera, Inorg. Chem. 2007, 46, 8668-75.

  9. “Photoactive Peptides for Light Initiated Tyrosyl Radical Generation and Transport into Ribonucleotide Reductase”; Steven Y. Reece, Mohammad R. Seyedsayamdost, JoAnne Stubbe and Daniel G. Nocera, J. Am. Chem. Soc. 2007, 129, 8500-9.

  10. “Excited State Dynamics of Hangman Dyads”; Justin Hodgkiss, Alex Krivokapic and Daniel G. Nocera, J. Phys. Chem. 2007, 111, 8258-68.

  11. “Catalase and Epoxidation Activity of Manganese Salen Complexes Bearing Two Xathene Scaffolds”; Jenny Y. Yang and Daniel G. Nocera, J. Am. Chem. Soc. 2007, 129, 8192-8.

  12. “Stereoelectronic Control of H2O2 Dismutation by Hangman Porphyrins”; Joel Rosenthal, Leng Leng Chng, Stephen D. Fried, and Daniel G. Nocera, Chem. Commun. 2007, 2642-4.

  13. “Proton-Directed Redox Control of O–O Bond Activation by Heme Hydroperoxidase Models”; Jake D. Soper, Sergey V. Kryatov, Elena V. Rybak-Akimova and Daniel G. Nocera, J. Am. Chem. Soc. 2007, 129, 5069-5075.

  14. “Hangman Salen Platforms Containing Two Xanthene Scaffolds” Jenny Y. Yang, Julien Bachmann and Daniel G. Nocera, J. Org. Chem. 2006, 71, 8706-14.

  15. “Mechanistic Studies of Hangman Salophen-Mediated Activation of O—O Bonds”; Shih-Yuan Liu, Jake D. Soper, Jenny Y. Yang, Elena V. Rybak-Akimova and Daniel G. Nocera, Inorg. Chem. 2006, 45, 7572-7574.

  16. "A Simple and Versatile Method for Alkene Epoxidation Using Aqueous Hydrogen Peroxide and Manganese Salophen Catalysts"; Shih-Yuan Liu and Daniel G. Nocera, Tet. Lett. 2006, 47, 1923-1926.

  17. "Electron Transfer Reactions of Fluorotyrosyl Radicals”; Steven Y. Reece, Mohammad R. Seyedsayamdost, JoAnne Stubbe, and Daniel G. Nocera, J. Am. Chem. Soc. 2006, 128, 13654-5.

  18. "Spectroscopic Determination of Proton Position in the Proton-Coupled Electron Transfer Pathways of Donor-Acceptor Supramolecule Assemblies"; Joel Rosenthal, Justin M. Hodgkiss, Elizabeth R. Young and Daniel G. Nocera, J. Am. Chem. Soc. 2006, 128, 10474-10483.

  19. "The Relation Between Hydrogen Atom Transfer and Proton-Coupled Electron Transfer in Model Systems"; Justin M. Hodgkiss, Joel Rosenthal and Daniel G. Nocera. In Handbook of Hydrogen Transfer. Physical and Chemical Aspects of Hydrogen Transfer, Vol. 1: J.T. Hynes, R.L. Schowen, H.H. Limbach, Eds.; Wiley VCH: Weinheim, Germany, 2006.

  20. "Electron Transfer Driven by Proton Fluctuations in a Hydrogen-Bonded Donor-Acceptor Assembly"; Justin M. Hodgkiss, Niels H. Damrauer, Steve Pressé, Joel Rosenthal and Daniel G. Nocera, J. Phys. Chem. A (Robert Silbey Festschrift issue) 2006, 110, 18853-18858.

  21. "Proton-Coupled Electron Transfer: The Mechanistic Underpinning for Radical Transport and Catalysis in Biology"; Steven Y. Reece, Justin M. Hodgkiss, JoAnne Stubbe and Daniel G. Nocera, Phil. Trans. Royal Soc. B 2006, 361, 1351-64.

  22. "Mono-, Di-, Tri-, and Tetra-Substituted Fluorotyrosines: New Probes for Enzymes That Use Tyrosyl Radicals in Catalysis"; Mohammad R. Seyedsayamdost, Steven Y. Reece, Daniel G. Nocera and JoAnne Stubbe, J. Am. Chem. Soc. 2006, 128, 1569-1579.

  23. "pH Rate Profiles of FnY356-R2s (n=2,3,4) in Escherichia coli Ribonucleotide Reductase: Evidence that Y356 is a Redox-Active Amino Acid along the Radical Propagation Pathway"; Mohammad R. Seyedsayamdost, Cyril S. Yee, Steven Y. Reece, Daniel G. Nocera and JoAnne Stubbe, J. Am. Chem. Soc. 2006, 128, 1562-1568.

  24. "Direct Tyrosine Oxidation Using the MLCT Excited States of Rhenium Polypyridyl Complexes"; Steven Y. Reece and Daniel G. Nocera, J. Am. Chem. Soc. 2005, 127, 9448-9458.

  25. "Hangman Salophens"; Shih-Yuan Liu and Daniel G. Nocera, J. Am. Chem. Soc. 2005, 127, 5278-5279.

  26. "pH Dependence of Charge Transfer Between Tryptophan and Tyrosine in Dipeptides"; Steven Y. Reece, JoAnne Stubbe and Daniel G. Nocera, Biochim. Biophys. Acta 2005, 1706, 232-238.

  27. “Observation of Proton-Coupled Electron Transfer by Transient Absorption Spectroscopy in a Hydrogen-Bonded, Porphyrin Donor-Acceptor Assembly”; Niels H. Damrauer, Justin M. Hodgkiss, Joel Rosenthal and Daniel G. Nocera, J. Phys. Chem. B 2004, 108, 6315-6321.

  28. “Site-Specific Replacement of a Conserved Tyrosine in Ribonucleotide Reductase with an Aniline Amino Acid: A Mechanistic Probe for a Redox-Active Tyrosine”; Michelle C.Y. Chang, Cyril S. Yee, Daniel G. Nocera, and JoAnne Stubbe, J. Am. Chem. Soc. 2004, 126, 16702-3.

  29. “Turning On Ribonucleotide Reductase by Light-Initiated Amino Acid Radical Generation”; Michelle C.Y. Chang, Cyril S. Yee, JoAnne Stubbe and Daniel G. Nocera, Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6882-7.

  30. “Targeted Proton Delivery in the Catalyzed Reduction of Oxygen to Water by Bimetallic Pacman Porphyrins”; Christopher J. Chang, Zhi-Heng Loh, Chunnian Shi, Fred C. Anson and Daniel G. Nocera, J. Am. Chem. Soc. 2004, 126, 10013-20.

  31. “Proton-Coupled Electron Transfer. A Unifying Mechanism for Biological Charge Transport, Amino Acid Radical Initiation and Propagation, and Bond making/breaking Reactions of Water and Oxygen”; Christopher J. Chang, Michelle C.Y. Chang, Niels H. Damrauer and Daniel G. Nocera, Biochim. Biophys. Acta 2004, 1655, 13-28.

  32. “Generation of the R2 subunit of Ribonucleotide Reductase by Intein Chemistry: Insertion of 3-Nitrotyrosine at residue 356 as a Probe of the Radical Initiation Process”; Cyril S. Yee, Mohammad R. Seyedsayamdost, Michelle C. Y. Chang, Daniel G. Nocera and JoAnne Stubbe, Biochemistry 2003, 42, 14541-52.

  33. “2,3-Difluorotyrosine on R2 of Ribonucleotide Reductase: A Probe of Long-Range Proton-Coupled Electron Transfer”; Cyril S. Yee, Michelle C.Y. Chang, Jie Ge, Daniel G. Nocera and JoAnne Stubbe, J. Am. Chem. Soc. 2003, 125, 10506-7.

  34. “Radical Initiation in the Class I Ribonucleotide Reductase: Long Range Proton Coupled Electron Transfer?”; JoAnne Stubbe, Daniel G. Nocera, Cyril S. Yee and Michelle C. Y. Chang, Chem. Rev. 2003, 103, 2167-202.

  35. “Catalytic O—O Activation Chemistry Mediated by Iron Hangman Porphyrins with a Wide Range of Proton-Donating Abilities”; Leng Leng Chng, Christopher J. Chang and Daniel G. Nocera, Org. Lett. 2003, 5, 2421-4.

  36. “Meso-Tetraaryl Cofacial Bisporphyrins Delivered by Suzuki Cross-Coupling”; Leng Leng Chng, Christopher J. Chang and Daniel G. Nocera, J. Org. Chem. 2003, 68, 4075-8.

  37. “Proton-Coupled O—O Activation on a Redox Platform Bearing a Hydrogen-Bonding Scaffold”; Christopher J. Chang, Leng Leng Chng and Daniel G. Nocera, J. Am. Chem. Soc. 2003, 125, 1866-76.

  38. “Ribonucleotide Reductases in the Twenty First Century”; JoAnne Stubbe, C. Drennan, Cyril Yee, D. Perlstein, J. Ge, Michelle Chang and Daniel Nocera, FASEB J. 2002, 16, A135-6.

  39. “Nanosecond Generation of Tyrosyl Radicals via Laser-Initiated Decaging of Oxalate-Modified Amino Acids”; Michelle C. Y. Chang, Scott E. Miller, Scott D. Carpenter, JoAnne Stubbe and Daniel G. Nocera, J. Org. Chem. 2002, 67, 6820-2.

  40. “A Convergent Synthetic Approach Using Sterically Demanding Aryldipyrrylmethanes for Tuning the Pocket Sizes of Cofacial Bisporphyrins”; Christopher J. Chang, Yong-qi Deng, Shie-Ming Peng, Gene-Hsiang Lee, Chen-Yu Yeh and Daniel G. Nocera, Inorg. Chem. 2002, 41, 3008-16.

  41. “Structural, Spectroscopic and Reactivity Comparison of Xanthene- and Dibenzofuran-Bridged Cofacial Bisporphyrins”; Christopher J. Chang, Erin A. Baker, Bradford J. Pistorio, Yongqi Deng, Zhi-Heng Loh, Scott E. Miller, Scott D. Carpenter and Daniel G. Nocera, Inorg. Chem. 2002, 41, 3102-9.

  42. “Porphyrin Architetures Bearing Functionalized Xanthene Spacers”; Christopher J. Chang, Chen-Yu Yeh and Daniel G. Nocera, J. Org. Chem. 2002, 67, 1403-6.

  43. “Structurally Homologous b- and meso-Amidinium Porphyrins”; Chen-Yu Yeh, Scott E. Miller, Scott D. Carpenter and Daniel G. Nocera, Inorg. Chem. 2001, 40, 3643-6.

  44. “Hangman Porphyrins for the Assembly of a Heme Water Channel”; Chen-Yu Yeh, Christopher J. Chang and Daniel G. Nocera, J. Am. Chem. Soc. 2001, 123, 1513-4.

  45. “Electron Tranfer in Hydrogen-Bonded Donor-Acceptor Supramolecules”; Christopher J. Chang, Joshua D. Brown, Michelle C.Y. Chang, Erin A. Baker and Daniel G. Nocera in Electron Transfer in Chemistry, V. Balzani, Ed., Wiley-VCH, Weinheim, Germany, 2001, Vol. 3, Chap. 2.4, p. 409-61.

  46. “Electrocatalytic Four-Electron Reduction of Oxygen to Water by a Highly Flexible Cofacial Cobalt Bisporphyrin”; Christopher J. Chang, Yong-qi Deng, Chunnian Shi, C.-K. Chang, Fred C. Anson and Daniel G. Nocera, Chem. Commun. 2000, 1355-6.

  47. “Xanthene-Bridged Cofacial Bisporphyrins”; Christopher J. Chang, Yong-qi Deng, Alan F. Heyduk, C. K. Chang and Daniel G. Nocera, Inorg. Chem. 2000, 39, 959-66.

  48. “Direct Observation of the "Pac-Man" Effect from Dibenzofuran-Bridged Cofacial Bisporphyrins”; Yong-qi Deng, Christopher J. Chang and Daniel G. Nocera, J. Am. Chem. Soc. 2000, 122, 410-1.

  49. “Facile Synthesis of ß-Derivatized Porphyrins – Structural Characterization of a ß-ß Bisporphyrin”; Yong-qi Deng, C.-K. Chang and Daniel G. Nocera, Angew. Chem. Int. Ed. Engl. 2000, 39, 1066-8.






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