Electronic Structure Investigation and Parametrization of Biologically Relevant Iron–Sulfur Clusters

Abstract

The application of classical molecular dynamics simulations to the study of metalloenzymes has been hampered by the lack of suitable molecular mechanics force field parameters to treat the metal centers within standard biomolecular simulation packages. These parameters cannot be generalized, nor be easily automated, and hence should be obtained for each system separately. Here we present density functional theory calculations on [Fe 2 S 2 (SCH 3 ) 4 ] 2 + / + , [Fe 3 S 4 (SCH 3 ) 3 ] +/0 and [Fe 4 S 4 (SCH 3 ) 4 ] 2+/+ and the derivation of parameters that are compatible with the AMBER force field. Molecular dynamics simulations performed using these parameters on respiratory Complex II of the electron transport chain showed that the reduced clusters are more stabilized by the protein environment, which leads to smaller changes in bond lengths and angles upon reduction. This effect is larger in the smaller iron−sulfur cluster, [Fe 2 S 2 (SCH 3 ) 4 ] 2+/+ . ■ INTRODUCTIONIron−sulfur proteins are ubiquitous in Nature, playing diverse functions such as electron transfer (ET), catalytic molecular conversions, structural roles, sensing, and regulation. 1 The most frequent activity is nevertheless biological ET. Iron−sulfur proteins are essential constituents of the mitochondrial respiratory chain, the photosynthetic ET chain and other systems of membrane bioenergetics. 1 These enzymes have reduction potentials that range from −700 to +400 mV. These finely tuned reduction potentials have evolved to facilitate ET with exceptional specificity and efficiency. 1 There are several types of iron−sulfur clusters with different stoichiometry of the irons and sulfurs. 2−4 The most common ones are mononuclear iron coordinated by four cysteines; two irons bridged by two sulfides and coordinated by four cysteine groups, i.e., [Fe 2 S 2 (SCH 3 ) 4 ] 2+/+ , the complete cubane [Fe 4 S 4 (SCH 3 ) 4 ] 2+/+ and the cubane structure with an absent iron [Fe 3 S 4 (SCH 3 ) 4 ] +/0 . Finally, there are the more exotic iron−sulfur clusters in the nitrogenase (N 2 ase) enzyme: 5,6 [Fe 7 Mo 1 S 8 (SCH 3 )] q (FeMoco cofactor) and [Fe 8 S 7 (SCH 3 ) 6 ] q (the P-cluster); the former is most likely responsible for the conversion of N 2 to NH 3 and the latter for the ET processes needed for it.These iron−sulfur clusters are complex systems, where the iron sites show large spin-polarization effects and Fe−S covalence and spin coupling; furthermore, they can display valence delocalization. Three major factors have been put forward 7−12 for the explanation of variations in the reduction potential within a single cluster type: the electrostatic environment of the redox center provided by surrounding charged amino acid residues, hydrogen bonds to the cluster, and the solvent exposure of the redox center. There exist extensive data on Fe−S experimental covalencies derived from a molecular orbital-based analysis of X-ray absorption spectroscopy (XAS) measurements, by Solomon and co-workers. 13 They found that the Fe−S covalency is significantly reduced...

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“…Previously, we computed the relative energies for the possible spin states of the reduced and oxidized iron–sulfur clusters 9. The [Fe 2 S 2 ] 2+ cluster has a total spin of zero ( S =0) and the reduced cluster [Fe 2 S 2 ] + has S =1/2 (isoenergetic with S =9/2).…”

“…Previously,w ec omputed the relative energiesf or the possible spin states of the reduced and oxidized iron-sulfur clusters. [9] The [Fe 2 S 2 ] 2 + cluster hasatotal spin of zero( S = 0) and the reduced cluster [Fe 2 S 2 ] + has S = 1/2 (isoenergetic with S = 9/2). The ground state for the [Fe 4 S 4 ]o xidized cluster was also found to have as pin state of S = 0, and the reduced cluster has S = 1/2.…”