Proteins containing iron-sulfur clusters are ubiquitous in nature and catalyze one-electron transfer processes. These proteins have evolved into two classes that have large differences in their electrochemical potentials: high potential iron-sulfur proteins (HiPIPs) and bacterial ferredoxins (Fds). The role of the surrounding protein environment in tuning these redox potentials has been a persistent puzzle in the understanding of biological electron transfer. Although high potential iron-sulfur proteins and ferredoxins have the same iron-sulfur structural motif, there are large differences in their electrochemical potentials. HiPIPs react oxidatively at physiological potentials, while Fds are reduced. Sulfur K-edge x-ray absorption spectroscopy (XAS; measured at SSRL beam line 6-2) has been used to uncover the substantial influence of hydration on this variation in reactivity in a collaborative effort led by Stanford Chemistry and Photon Science researchers. The study showed that the Fe-S covalency (a measure of the electronic overlap of the sulfur and iron orbitals forming the bonds within the clusters) is much lower in natively hydrated Fd active sites than in HiPIPs, but increases upon water removal; similarly, HiPIP covalency decreases when reversibly unfolded, exposing an otherwise hydrophobically shielded active site to water. These results demonstrate that the Fe-S covalency determined from the sulfur-K XAS data is a direct experimental marker of the local electrostatics due to H-bonding. Studies on related model compounds and accompanying density functional theory calculations support a correlation between Fe-S covalency and ease of oxidation, which suggests that differential hydration accounts for most of the difference between Fd and HiPIP reduction potentials. This raises the intriguing possibility that oxidation/reduction potentials can be regulated by protein/protein and protein/DNA interactions that effect cluster hydration.

A. Dey, F. E. Jenney, Jr., M. W. W. Adams, E. Babini, Y. Takahashi, K. Fukuyama, K. O. Hodgson, B. Hedman and E. I. Solomon, "Solvent Tuning of Electrochemical Potentials in the Active Sites of HiPIP Versus Ferredoxin", Science 318, 1464 (2007)

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