Available online at www.sciencedirect.com Electron transfer in peptides and proteins Bernd Giese, Michael Graber and Meike Cordes Proteins and peptides use their amino acids as medium for electron-transfer reactions that occur either in single-step superexchange or in multistep hopping processes. Whereas the rate of the single-step electron transfer dramatically decreases with the distance, a hopping process is less distance dependent. Electron hopping is possible if amino acids carry oxidizable side chains, like the phenol group in tyrosine. These side chains become intermediate charge carriers. Because of the weak distance dependency of hopping processes, fast electron transfer over very long distances occurs in multistep reactions, as in the enzyme ribonucleotide reductase. Address Department of Chemistry, University of Basel, St. Johanns Ring 19, CH- 4056 Basel, Switzerland Corresponding author: Giese, Bernd (bernd.giese@unibas.ch), Graber, Michael (michael.graber@unibas.ch) and Cordes, Meike (meike.cordes@unibas.ch) Current Opinion in Chemical Biology 2008, 12:755–759 This review comes from a themed issue on Model Systems Edited by Helma Wennemers and Ronald T. Raines Available online 17th September 2008 1367-5931/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cbpa.2008.08.026 Introduction Electron-transfer (ET) reactions through proteins play a crucial role in energy conversion processes like photosyn- thesis and respiration, where electrons are transferred through protein complexes across the cell membrane (30–35 A ˚ ), thereby building up an electric potential. In addition, the metabolic catalysis of several enzymes also depends on long-distance ET through proteins. Two major models provide explanations for these long-range ET processes: (a) The superexchange model, which is based on the Marcus theory [1], regards the peptidic matrix as a medium for electronic coupling between an electron donor (D) and an electron acceptor (A). The overlap of donor and acceptor orbitals that controls the ET reaction rate k ET depends exponentially on the distance r DA between the redox sites (Eqn (1)). A pre-exponential factor, the distance decay parameter b, represents the influence of the separating medium on the ET rates [2]: k ET / e br DA (1) According to the superexchange model the ET pro- cess occurs in a single-step reaction. (b) The hopping model, which is based on the diffusion of the charge via oxidized (or reduced) intermediates, describes the ET as a multistep process. The charge migrates (hops) through the protein using certain amino acids as relay stations (stepping stones). For charge hopping processes like this the rate k ET depends upon the number of hopping steps N (Eqn (2)) with x between 1 and 2 that denotes whether the steps are irreversible or reversible [3]: k ET / N x (2) According to the hopping model one long and there- fore relatively slow ET process is replaced by several shorter and faster ET steps. In the past two to three years both models have contributed to the explanation of long-range ET through peptides and enzymes. ET by superexchange In order to study the characteristic features of peptide matrices in ET reactions, Gray and Winkler developed an experimental method based on modified metalloproteins [4]. They introduced metal-binding histidine residues at defined positions of proteins that contain copper (azurin), iron (cytochromes c and b 562 , myoglobin), or zinc (modi- fied cytochrome c) cofactors. Photoexcitable ruthenium or osmium complexes were bound to the histidines, and metal-to-metal ET reactions through the proteins were measured in laser experiments. For the majority of the 30 investigated Ru-labeled metalloproteins, the ET rates are described by Eqn (1). Their b-values depend upon the secondary structure of the protein. For example, in a series of six azurins, forming b-sheets, a distance decay parameter (b) of 1.1 A ˚ 1 was determined [5]. However, with Ru-modified proteins that contain heme-cofactors (cyt b 562 , cyt c, and myoglobin) not all measurements could be described by Eqn (1) (Figure 1). Electron transfer through histidine-modified cytochrome b 562 Thus, in experiments with cyt b 562 two of nine datapoints showed anomalously slow ET reactions [6  ]. This devi- ation could be explained by the pathway model, originally proposed by Beratan et al. in the late 1980s [7], which has been refined during the past years [6  ,8,9]. In the pathway model, a set of possible ET pathways, consisting of p-bonds, s-bonds and H-bonds, as well as through space contacts, determines the coupling between electron donor and electron acceptor. For each pathway, the coupling strength is a function of all possible bonding contacts (b  1A ˚ 1 ), and nonbonding contacts www.sciencedirect.com Current Opinion in Chemical Biology 2008, 12:755–759