Protein Control of Redox Potentials of Iron−Sulfur Proteins - Chemical

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Chem. Rev. 1996, 96, 2491−2513

2491

Protein Control of Redox Potentials of Iron−Sulfur Proteins P. J. Stephens,* D. R. Jollie, and A. Warshel Department of Chemistry, University of Southern California, Los Angeles, California 90089-0482 Received March 18, 1996 (Revised Manuscript Received July 1, 1996)

Contents I. Introduction II. Modeling Redox Potentials Using the PDLD Approach A. The PDLD Methodology 1. Overview 2. Equations 3. Implementation and Parameters B. PDLD Calculations III. Molecular Dynamics A. Methodology B. MD-PDLD Calculations IV. Mutants V. Charged Residues VI. Predictions VII. Prior Literature VIII. Discussion

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I. Introduction Iron-sulfur ([Fe-S]) proteins1-3 contain ironsulfur ([Fe-S]) clusters in which iron atoms are wholly or predominantly coordinated by sulfur atoms. The sulfur atoms are of two types: cysteine Sγ and monatomic, “inorganic” S. The simplest [Fe-S] clusters are those in which Fe is the only metal present and all Fe atoms are wholly ligated by S. Examples are the 1Fe, 2Fe, 3Fe, and 4Fe clusters whose stoichiometries are:

1Fe 3Fe

FeCys4 Fe3S* 4Cys3

2Fe 4Fe

Fe2S* 2Cys4 Fe4S* 4Cys4

where S* denotes inorganic sulfur. The 3D structures of these clusters are shown in Figure 1. Fe is four coordinate, each cysteine Sγ ligates one Fe and inorganic S bridges multiple Fe atoms. Clusters are also known in which other metals, in addition to Fe, and/or other ligands, in addition to cysteine, are present. [Fe-S] clusters exhibit reversible oxidation-reduction between different oxidation levels. Oxidation levels can be defined by the total cluster charge and by the formal oxidation levels of the Fe atoms obtained assuming cysteine and inorganic sulfur to have charges of -1 and -2, respectively. In the simple 1Fe, 2Fe, 3Fe, and 4Fe clusters, the following redox couples are well known:

FeCys4

cluster charges 1-/2-

formal Fe oxidation levels Fe3+/Fe2+

Fe2S2*Cys4

2-/3-

Fe23+/Fe3+,Fe2+

Fe3S4*Cys3

2-/3-

Fe33+/Fe23+,Fe2+

Fe4S4*Cys4

2-/31-/2-

Fe23+,Fe22+/Fe3+,Fe32+ Fe33+,Fe2+/Fe23+,Fe22+

The redox potentials of [Fe-S] clusters in [Fe-S] proteins vary widely,4 the most positive being >+400 mV (vs SHE) while the most negative are