Redox thermodynamics of low-potential iron-sulfur proteins

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Abstract
The enthalpy and entropy changes associated with protein reduction (ΔH°'rc, ΔS°'rc) were determined for a number of low-potential iron-sulfur proteins through variable temperature direct electrochemical experiments. These data add to previous estimates making available, overall, the reduction thermodynamics for twenty species from various sources containing all the different types of metal centers. These parameters are discussed with reference to structural data and calculated electrostatic metal-environment interaction energies, and redox properties of model complexes. This work, which is the first systematic investigation on the reduction thermodynamics of Fe-S proteins, contributes to the comprehension of the determinants of the differences in reduction potential among different protein families within a novel perspective. Moreover, comparison with analogous data obtained previously for electron transport (ET) metalloproteins with positive reduction potentials, i.e., cytochromes c, blue copper proteins, and HiPIPs, helps our understanding of the factors controlling the reduction potential in ET species containing different metal cofactors. The main results of this work can be summarized as follows. 1. At variance with high-potential ET proteins, which invariably possess negative ΔH°'rc values, the reduction enthalpy of low-potential ferredoxins (Fds) may have both signs; most notably, the sign is conserved within each protein family containing a given Fe-S center (with only a few exceptions), in line with the similarity of the interactions of the cluster with the protein environment and the solvent, and changes on passing from one family to that differing for one Fe in the cluster. In particular, ΔH°'rc is negative for proteins containing 1-Fe and 3-Fe centers and positive for those with 2-Fe and 4-Fe centers. Given that the ΔS°'rc values are independent of the cluster type, the reduction enthalpy is thus ultimately responsible for the modulation of the reduction potential of Fds as a function of the Fe nuclearity of the cluster. 2. A major role in this modulation is played by the inherent properties of the Fe-S cluster in terms of selective stabilization of one of the two redox states. 3. Fds almost invariably show an entropy loss upon reduction, like all the high-potential ET metalloproteins; this property thus appears to be functional to the optimization of the electron flow between metalloredox partners for reasons that are still unclear. 4. The negative reduction entropy strongly contributes to lower the potential of Fds, particularly for the mononuclear and trinuclear Fe centers in which it counterbalances the enthalpy change which would favor reduction. 5. The reduction entropy may change remarkably among the members of the same class possessing a given cluster type, thus appearing one of the main factors responsible for the only partial success of electrostatic models in reproducing variations in E° among homologous species. 6. In agreement with theoretical studies, the different redox couple accessible to the Fe-S cluster in HiPIPs as compared to the low-potential 4Fe Fds is entirely due to enthalpic effects related to the electrostatic interactions of the cluster with the proteins matrix and the solvent.

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