J. Phys. Chem. B 2001, 105, 4453-4463
4453
A Density Functional Study of Possible Intermediates of the Reaction of Dioxygen Molecule with Nonheme Iron Complexes. 2. “Water-Assisted” Model Studies Maricel Torrent, Djamaladdin G. Musaev,* and Keiji Morokuma* Cherry L. Emerson Center for Scientific Computation and Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
Harold Basch Department of Chemistry, Bar Ilan UniVersity, Ramat Gan 52900, Israel ReceiVed: January 11, 2001; In Final Form: March 6, 2001
The structure and stabilities of various intermediates of the “water-assisted” O-O bond activation reaction on the MMOHred and R2red were studied using the B3LYP hybrid density functional method, and are compared with those for the “water-free” model studies. It was shown that the first step of the reaction is coordination of the O2 molecule to one of the Fe atoms of complex I_H2O (“water-assisted” model complex) leading to formation of the mixed-valence superoxo species, [FeII(O2)-FeIII], II_H2O. Then, the second electron transfer from the other Fe atom to the O2 moiety leads to formation of the peroxo complex [FeIII(O2)2-FeIII], which is found to have four different isomers, III_H2O, IV_H2O, V_H2O, and VI_H2O, corresponding to the cisµ-1,2, end-on µ-1,1, distorted trans-µ-1,2, and µ-η2-η2 coordination modes of O2, respectively. The stability (relative to I_H2O + O2) of these isomers increases via III_H2O (34.5 kcal/mol) < VI_H2O (36.4 kcal/mol) < V_H2O (44.7 kcal/mol) < IV_H2O (57.4 kcal/mol). On the basis of the structural analysis and calculated O-O bond distances, we have predicted that isomers III_H2O, V_H2O, and VI_H2O are intermediates on the potential energy surface of the homolytic O-O activation process, while isomers III_H2O and IV_H2O are intermediates of the heterolytic O-O activation reaction. The homolytic O-O activation by MMOHred is predicted to occur via the following intermediates: I_H2O + O2 f II_H2O (superoxo species) f III_H2O (cis-µ-1,2-peroxo) f V_H2O (distorted trans-µ-1,2-peroxo) f VI_H2O (µ-η2-η2 peroxo) f VII_H2O (compound Q with water) f VIII (compound Q). Having an additional water molecule around the active site of MMOHred (and R2red) facilitates the superoxo f peroxo conversion process because of the opening of one of the “legs” of µ-1,2-bridged carboxylate leading to formation of Fe1-HOH...OCHO-Fe2 network.
I. Introduction The activation of the O-O bond of dioxygen and utilization of its oxygen atoms via incorporation into organic substrates by enzymes (called oxygenases) has a fundamental and practical importance.1 It is well established that heme-containing enzymes such as cytochromes P450, peroxidases, and catalases activate and utilize dioxygen and its partially reduced forms in a variety of enzymatic reactions.2 Over the past decade a new class of enzymes, nonheme enzymes containing carboxylate-bridged diiron active sites, which also activate dioxygen molecule and incorporate its oxygen atoms into organic substrate, have been discovered.3 Among these enzymes, methane monooxygenase (MMO), and ribonucleotide reductase (RNR) have a special interest, and here, we intend to study computationally the features of dioxygen O-O bond cleavage in MMO and RNR in more detail. MMO is a classic monooxygenase in which two reducing equivalents from NAD(P)H are utilized to split the O-O bond of O2. Later, one O atom is reduced to water by a two-electron reduction, while the second O atom is incorporated into the substrate to yield methanol:
CH4 + O2 + NAD(P)H + H+ f CH3OH + NAD(P)+ + H2O (1)
Soluble forms of MMO contain three proteins: an ironcontaining hydroxylase (MMOH) which binds O2 and hydrocarbon substrate, a reductase (MMOR) containing Fe2S2 and FAD cofactors which enable it to accept electrons from NADH and transfer them to the hydroxylase, and a regulatory or coupling component, protein B (MMOB). Each of these three proteins is required for efficient substrate hydroxylation coupled to NADH oxidation.3-6 RNR catalyzes the reduction of ribonucleotides to deoxyribonucleotides which is the rate-determining step in DNA biosynthesis.3,7 In the literature, there are at least four classes of RNR.8 The best-characterized class, class I, includes two different subunits, R1 and R2. R2 subunit contains a binuclear non-heme Fe active site. This class of RNR requires O2 and a binuclear active site to generate the stable tyrosyl radical via oxidation of the binuclear ferrous center of R2 to an oxo-bridged binuclear ferric site:
R2-apo + Tyr122-OH + 2FeII + e- + O2 + H+ f R2-(FeIII-O-FeIII) + Tyr122-O‚ + H2O (2) Extensive experimental studies9 have shown that the oxidized forms of MMOH and R2 (MMOHox and R2met) containing two ferric iron atoms, FeIII, are the resting states of these enzymes. Only their two-electron reduced forms, MMOHred and R2red,
10.1021/jp010136z CCC: $20.00 © 2001 American Chemical Society Published on Web 04/20/2001
4454 J. Phys. Chem. B, Vol. 105, No. 19, 2001 SCHEME 1: Experimentally Defined Active Sites of MMOHRed and R2Red (See Reference 3)
Torrent et al. SCHEME 2: Experimentally Proposed Catalytic Cycle for Methane Hydroxylation by MMOH (See References 3c and 3d)
SCHEME 3: Proposed (a) Homolytic and (b) Heterolytic O-O Bond Activation Mechanisms (See Reference 3d)
with two ferrous FeII iron centers react with O2. Experimental studies10 have unveiled some similarity of the active sites of MMOHred and R2red, as seen in Scheme 1. In both cases, the core of their active sites includes two ferrous iron centers bridged by two carboxylate ligands.11 Each of the Fe-centers has one histidine and one terminal oxo-ligand. In addition, one of the Fe’s (Fe1) includes an additional water molecule. However, in MMOHred, one of the carboxylate ligands, Glu243, forms a monodentate bridge between the two metals, and at the same time coordinates to the Fe2-center in a bidentate manner. On the other hand, in R2red both carboxylate ligands form a bidentate, µ-1,2, bridge between the Fe centers. Thus, according to spectroscopic and structural studies, both Fe centers of the MMOHred are five coordinated, (5C, 5C).12 However, in R2red the Fe1 and Fe2 atoms have different environments, 5C and 4C, respectively. Thus, the structures of the active sites of the MMOHred and R2red effectively differ ONLY by the coordination mode of one of bridging glutamates; Glu243 in MMOHred forms a µ-1,1-type of bridge between two Fe centers, while its analogue Glu238 in R2red forms a µ-1,2-type of bridge. Recent theoretical and experimental studies show high ligand flexibility of the active sites of MMOHred and R2red, which has been postulated to be one of the important factors for the proper functioning of the enzymes.13-15 Despite the observed structural similarities of their active sites, MMO and RNR perform different catalytic functions that involve different dioxygen reactivity. Numerous experimental studies1-13,16 of the reaction of MMOHred with dioxygen molecule indicate that MMOHred slowly reacts with dioxygen. Its reactivity is greatly enhanced (by ∼1000-fold) by the addition of a small coupling protein, component B. The first intermediate of the reaction of MMOHred and O2 is found to be a metastable so-called compound O (oxygen adduct), which spontaneously converts to compound P, as shown in Scheme 2. Although the structure of P is not determined yet, it is believed to be a peroxide species (with µ-1,2-peroxo bridged structure) where both oxygens are bound symmetrically to the iron centers. Experiments indicate the existence of the metastable either peroxo or superoxo adduct between the intermediates O and P, called intermediate P*. However, currently there is no spectroscopic data available for this species. Intermediate P spontaneously converts to compound Q, which oxidizes the substrates.
In contrast to MMOHred, R2red, the active site of which is different from the former only by the coordination mode of one of the bridging glutamates, reacts rapidly with the dioxygen and leads to two intermediates, X, and U. The intermediate U is believed to be a protonated tryptophan radical and the intermediate X to be a mixed-valence [FeIIIFeIV] complex containing two or three µ-oxo-bridges. In contrast to MMOHred, no peroxo intermediate has been observed for the reaction of R2red with O2. The mechanism of the O-O bond activation by MMOHred and R2red is not yet clear, even though there has been a general consensus regarding the formation of intermediate Q from intermediate P. In literature,3d for the reaction of O-O with MMOHred two different mechanisms, homolytic and heterolytic, were proposed, as shown in Scheme 3. The heterolytic O-O activation mechanism proceeds by asymmetric double protonation of end-on bridged peroxide, while the homolytic mechanism proceeds via the rearrangement of the O-O moiety of intermediate P. However, still there is no clear understanding in either (1) the real mechanism (heterolytic vs homolytic) of the O-O bond activation by MMOHred and R2red, (2) the factors affecting this process, or (3) structures and relative energies of the assumed intermediates and the transition states. Therefore, we have lunched comprehensive computational studies of the reaction mechanism of MMOHred with the dioxygen molecule:
MMOHred + O2 f {FeIII‚O22-‚FeIII}P f {FeIV‚(O2-)2‚FeIV}Q (3) One should note that an investigation of the mechanism of O2 activation by MMO requires elucidation of several aspects. First, it would be desirable to know the substrate coordination side. So far, X-ray crystallographic studies of MMOH from Methylococcus capsulatus (Bath)5 have revealed four such positions,
Nonheme Iron Complexes SCHEME 4: Experimentally Proposed Substrate Coordination Sites (See Reference 5)
SCHEME 5: Models Used in the Present Studies
J. Phys. Chem. B, Vol. 105, No. 19, 2001 4455 MMO. However, some earlier studies either used unrealistic models, such as FeO+, Fe2(OH)3(H2O)2(HCOO)(µ-O)2, Fe2(OH)4(H2O)4(µ-O)2, and (H2O)2Fe(µ-O)2Fe(H2O), or low-level theoretical models such as the extended-Hu¨ckel method, and will not be discussed. Recently, two groups have launched computational studies on more realistic models. The model, (HCO2)(Imd)Fe(µ-1,2-HCO2)2Fe(HCO2)(Imd), used by Siegbahn21 is consistent with experimental findings and applied to study the structure and stabilities of the expected intermediates of the homolytic O-O bond activation process. He calculated the structures and energies of two different peroxo compounds and Q compound. In their studies Friesner, Lippard, and co-workes22 used even larger models such as (MeImd)(MeCO2)Fe(µ-OH)2(µ-MeCO2)2Fe(MeCO2)(MeImd)(H2O) and (MeImd)(MeCO2) Fe(µ-OH)2(µ-Glu)2Fe(MeCO2)(MeImd)(H2O), Imd ) imidazole, to elucidate geometrical parameters of MMOHox, MMOHred, R2met, and R2red. In general, these models in conjunction with density functional theory (DFT) provide very promising results. Note that we have recently reported the quantum chemical studies of mechanism of the reaction of intermediate Q with molecule methane:23-25
{FeIV(O2-)2FeIV}Q + CH4 f {Fe2(µ-O)(µ-HOCH3)} (4)
as shown in Scheme 4. The positions 1, 3, and 4 are located on the O-side of the iron cluster, i.e., the side opposite to the side (hereafter called N-side), where protein residues His147 and His246 lie. The fourth position, 2, is located on the N-side. According to experimental data,3 the only valid pathway is the coordination of the substrate from the O-side, because of the existence of the substrate coordination pocket; the coordination of substrate from the N-side is sterically hindered and is not feasible. Despite this, we have studied in detail both the O-side and N-side mechanisms of the reaction 3, which are presented in a separate paper,17 and will be only briefly summarize below. The second aspect to be taken into account is the role of the water. Are water ligands mere spectators or do they actively participate in the catalytic cycle? It is known from X-ray structures of MMOHox and MMOHred5 that at least one (in some cases two) water molecule(s) is/are present in the immediate vicinity of the diiron cluster, as seen in Scheme 1. The possible role (if any) of such aqueous ligands has not yet been well understood. In the present paper we report structures and stabilities of the intermediates of the reaction 3 for model complex I_H2O, which has one more water molecule compared to model I, used previously,17 as shown in Scheme 5. We believe that the comparison of the results for model I_H2O (below we will call it “water-assisted” model) with those reported previously17 for the “water-free” model I will allow us to elucidate the role of water molecule in this O-O activation process. Previously several other groups have published theoretical papers18-20 on the mechanism of methane hydroxylation by
These studies, as well as works of other groups,21 demonstrated that the reaction of MMOHred with substrates is a multistate (electronic state) process. Therefore, in studies of the mechanism of the reaction 3, several lower lying electronic states should be taken into account. The present paper is organized as follows. In section II we discuss the details of the computational approaches. Section III briefly summarizes the results of our previous studies of the “water-free” mechanism of the reaction 3, including O-side and N-side pathways. In section IV we present our results for the “water-assisted” mechanism of the reaction 3, and in section V we compare “water-assisted” and “water-free” mechanisms. In section VI we make a few conclusions. II. Computational Details To be consistent with our previous study,17 we have chosen a similar model for the MMOHred, as shown in Scheme 5, (H2O)2(NH2)Fe(η2-HCOO)2Fe(NH2)(H2O), I_H2O, which, in addition to model I used in our previous studies, includes one water molecule on the Fe1-center. Such a model satisfies the requirements imposed by experimentally available data;3 the model includes one histidine nitrogen (modeled by NH2) and one oxo-ligand (modeled by OH2) for each Fe center, and two bridging carboxylates (modeled by HCOO-) coordinated to the two Fe centers. However, in this model the bridging carboxylates are bidentately positioned between the Fe-centers, which should be the case only for R2red, rather than MMOHred, as shown in Scheme 5. Indeed, as discussed in the Introduction, MMOHred contains one monodentately bridged and one bidentately bridged carboxylates. We choose the model with two bidentately bridged-carboxylates ligands because of our extensively studies24,15 of the flexibility of the ligand environment of Fe-centers of the active sites of MMOHred and R2red have shown that 1. (a) The structure with two bidentate (µ-1,2) bridging carboxylates, R2red-like, is energetically a few kcal/mol more stable than the structure with one monodentate (µ-1,1) and one bidentate (µ-1,2) bridging carboxylate, MMOHred-like, and (b) MMOHredlike structure is separated from the R2red-like one with only a very small energetic barrier. Thus, the calculated thermodynamic
4456 J. Phys. Chem. B, Vol. 105, No. 19, 2001 and kinetic results show that the MMOHred-like T R2red-like rearrangement is going to be an easy process. This conclusion is in excellent agreement with available experimental data.26 2. More importantly, the substrate (O2) coordination destabilizes the transition state separating of MMOHred-like and R2reelike structures. As a result, the minimum corresponding to MMOHred-like structure on the potential energy surface disappears, and the MMOHred-like structure spontaneously converts to the R2red-like structure (for details see below). Our model has no net charge, which is consistent with the fact that the active site of protein is buried in a low dielectric protein medium.3 In I_H2O, imidazole rings of the His ligands are located cis to each other, i.e., two monodentate terminal carboxylates are cis to each other as well, which is also consistent with experiments.3 Thus, by counting protein ligands only, the model has two four coordinated, 4C, iron centers. Since the available X-ray and spectroscopic data3 indicate the existence of the additional water molecule(s) around the Fe-centers, we have added one water molecule to the Fe1 center. This water addition also is in fulfillment of the spectroscopic results for the reduced binuclear active site of RNR showing a (5C, 4C) core.27 Another important question is a choice of the spin state for the calculations of these systems. According to spectroscopic studies,3,28 MMOHred contains two ferromagnetically coupled FeII-centers (four unpaired electrons each), and has a total S ) 4 in the ground state. The spectroscopic picture for R2red is slightly more complex. Mo¨ssbauer studies show the two Fecenters in R2red are high-spin ferrous ions,29 whereas EPR studies of R2red show a very weak integer spin signal, considered to derive from a small fraction of molecules having ferromagnetically coupled sites.30 Magnetic circular dichroism studies show a paramagnetic center with a saturation behavior indicating two Fe-centers with Ms ) (2 in the ground state. However, a spin Hamiltonian analysis of the saturation magnetization behavior indicates that the two Fe atoms are weakly (J ∼ 0.5 cm-1) antiferromagnetically coupled.27,31 Since the exchange coupling constant of R2red is extremely small, we have considered both MMOHred and R2red as ferromagnetically coupled high-spin species, and we have studied them at their 2Ms+1 ) 9 spin states. High-spin states are, in general, theoretically cleaner than low-spin states, which are often contaminated by high-spin states of the same Ms value. Test calculations with 2Ms+1 ) 7 performed for MMOHred indicate that this state is high in energy and therefore will not be discussed below. Comparisons of energies for the intermediates involved in these reactions at ferromagnetic (high spin) state and antiferromagnetic state have been recently reported in two independent theoretical studies.21,22 Once MMOHred (9A) reacts with the ground-state O2 (3Σ), there are at least two additional possible spin states to be considered: 2Ms+1 ) 7 and 11. Therefore, in this paper we have calculated electronic states for intermediate with 2Ms+1 ) 7, 9, and 11 to ensure the correct multiplicity in each case. Further details are given in the text. In these calculations, the spin-unrestricted open-shell singledeterminant B3LYP32 method has been used in conjunction with the Stevens-Basch-Krauss (SBK) effective core potentials (ECP) and the standard 31G, CEP-31, and (8s8p6d/4s4p3d) basis sets for H, (C, O, and N), and Fe atoms, respectively.33 Full geometry optimizations have been carried out for all stationary points. All calculations have been performed using Gaussian98.34
Torrent et al. Note that in this paper we report only structures and stabilities of the intermediates of the reaction 3 for model I_H2O. Studies of the transition states separating the reported intermediates are in progress. III. Summary of the “Water-Free” Mechanism of Homolytic O2 Activation Previously, we have studied17 in detail the mechanism of homolytic O-O bond activation, reaction 3, by the model complex I, “water-free” model. In these studies we have investigated both N-side and O-side pathways. The following conclusions have been found. 1. Both pathways proceed via the same (or similar) intermediates, while the N-side mechanism proceeds with a lower activation barrier and is also thermodynamically more favorable. In other words, if the protein backbone did not block the N-side, the O2 molecule would most likely approach the binuclear iron center from this side rather than from the O-side. However, N-side mechanism is not feasible from experimental point of view;3, therefore below, we will discuss only the O-side pathway. 2. The detailed potential energy profile for the O-side pathway is shown in Figure 1. The reaction starts with coordination of the O2 molecule to the Fe-centers, leading to formation of the mixed-valence species [FeII(O2)-FeIII], II, with end-on coordinated terminal O2-moiety. Complex II is assigned to be intermediate P*. The ground state of this complex is 11A state. It rearranges to the O-O cis-µ-1,2 type complex P, III, with a [FeIII(O2)2-FeIII] core. (For schematic representation of various coordination modes of O2 in a binuclear complex, see Scheme 6.) Complex III is calculated to be only 1.0 kcal/mol higher in energy than complex II. Later, complex III converts either to complex IV, where the O2-moiety is coordinated to Fe-centers as an end-on µ-1,1 ligand, or to complex V, where the O2-moiety is coordinated to Fe-centers as a distorted trans-µ-1,2 ligand. Both IV and V are [FeIII(O2)2-FeIII] type diferric complexes. Our calculations indicate that barriers separating III from IV and V are extremely small. The barrier separating III from V corresponds to raising one of the “legs” of bidentately bridged carboxylate. From complex IV, the reaction proceeds via the heterolytic O-O activation mechanism, which is presently under investigation. From complex V, where one of the bridged carboxylates lost its bridged character and coordinated only to one of Fe centers (Fe2), reaction proceeds via the homolytic O-O dissociation mechanism and leads to the formation of the complex [FeIII(O)23-FeIV], VI, with a ground 11A state. The transition state corresponding to this process is under investigation. Later, the rearrangement of the carboxylate from terminal to the bridging position accompanied by subsequent electron transfer (fourth electron transfer) from another Fe center (Fe1) leads to formation the final product, intermediate Q, [FeIV(O2-)2FeIV] VII, with a ground 9A state. Complex VII in the ground 9A state lies only 0.4 kcal/mol above the ground 11A state of complex VI, and can be easily reached. Thus, homolytic O-O bond activation by model complex I includes the following steps: (i) coordination of O2 to Fe-centers to form the mixedvalence complex II accompanied by the first electron transfer to dioxygen; (ii) the second electron transfer from ferrous iron center to the O2-moiety to form the cis-µ-1,2 type P complex, III; (iii) raising one leg of the bridging carboxylate ligand (Glu243) and subsequent rearrangement of the O-O moiety from a cis-µ-1,2 binding mode to a distorted trans-µ-1,2 binding mode in intermediate V; (iv) the activation of the O-O bond
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J. Phys. Chem. B, Vol. 105, No. 19, 2001 4457
Figure 1. Relative energies of the calculated intermediates of reaction 3 within the “water-free” model studies (see ref 17).
SCHEME 6: Coordination Modes of Dioxygen Adducts Adopted in Dinuclear Complexes (See Reference 38)
accompanied by third-electron transfer from Fe to O leading to the intermediate VI, with an FeIII-FeIV mixed valence core; and finally (v) rearrangement of the carboxylate from terminal to the bridging position accompanied by the fourth electron transfer and a spin crossing, leading to the final product, FeIVFeIV, Q.
[FeIIFeII], I f [FeII(O2)-FeIII], II(P*) f [FeIII(cis-O2)2-FeIII], III(P) f [FeIII(trans-O2)2-FeIII], V f [FeIII(O)23-FeIV], VI f [FeIV(O2-)2FeIV], VII(Q) IV. Results and Discussion As mentioned above, N-side pathway is not feasible from the experimental point of view;3 therefore, here we discuss only the O-side pathway of the reaction of I_H2O with O2. Structures of all calculated intermediates of reaction 3 within the novel “water-assisted” mechanism proposed here are given in Figure 2. Their relative energies are presented in Figure 3. The calculated Mulliken spin populations, together with O-O bond distances and selected Mulliken charges, are presented in Table 1. Cartesian coordinates of all calculated intermediates, and their 〈S2〉 values, are given as Supporting Information.
Reactants: Complex I_H2O and O2 Molecule. As discussed above, according to numerous experiments the iron centers of MMOHred are ferromagnetically coupled, with four unpaired electrons on each Fe. This is consistent with the calculated Mulliken atomic spin densities for the model system I_H2O, presented in Table 1. As seen from this table, Fe centers of complex I_H2O have four unpaired spins on each, i.e., they are ferrous Fe(II) atoms. However, the calculated geometric structure of I_H2O is not totally symmetric, as seen in Figure 2, reflecting the nonequivalent environments of its iron atoms; Fe1, on the left side of the structure, has an additional water ligand and is 5C, while the other iron center, Fe2, on the right side is 4C. As seen in Figure 2 and discussed above, in complex I_H2O two iron centers are bridged by two carboxylate ligands in a µ-1,2 binding mode. This conformation is characteristic for the reduced form of the active site of RNR. However, in MMOHred one of the carboxylate ligands should form a monodentate, µ-1,1, bridge between the iron atoms. In an attempt to maintain fidelity with available experimental data, we have investigated an alternative conformation for I_H2O having a µ-1,1 binding mode for one of the carboxylates (called structure I′_H2O, shown in Scheme 5). However, we could not find the minimum corresponding to structure I′_H2O within the current model system. It converges to the structure I_H2O presented in Figure 2. Therefore, below, in our discussions of the mechanism of reaction 3, we will use the structure I_H2O with two µ-1,2bridged carboxylates as a reactant complex. The ground triplet (3Σ) state of O2 has the configuration KK(σs)2(σs*)2(σp)2(πx)2(πy)2 (πx*)1(πy*)1, with one unpaired electron on each oxygen atom. Its open-shell singlet excited-state having one electron in each antibonding π* orbital is calculated to be 29.2 kcal/mol higher than ground triplet state. This tripletsinglet splitting, although not very accurate at this level of theory, is still in qualitative agreement with the experimental value of 22.5 kcal/mol.35 The first step of reaction 3 is expected to be substrate coordination to the active site of the enzyme. This could be a very complex process, and may proceed with a significant
4458 J. Phys. Chem. B, Vol. 105, No. 19, 2001
Torrent et al.
Figure 2. Structures of all calculated intermediates of reaction 3 within the novel “water-assisted” model studies.
Figure 3. Relative energies of the calculated intermediates of reaction 3 within the “water-assisted” model studies.
energetic barrier required for reorganization of the active site and its protein environment. Coordination of O2 molecule to MMOHred may produce a weakly protein-bound complex like compound O predicted by experimentalists.3 However, this type of protein-bound complexes cannot be calculated for the presented model lacking the protein environment. Instead, we have made several attempts to find the weakly bound O2‚‚‚ I_H2O complex having the oxidation state of [FeII(O2)FeII]. This complex may have several electronic states, among which we investigated only those with 2MS+1 ) 11, 9, and 7. However, we were not able to locate a minimum corresponding to [FeII(O2)FeII], and conclude that the weakly bound O2‚‚‚I_H2O complex does not exist. Meantime, geometry optimization of
the structure [FeII(O2)FeII] by scanning for an Fe-O2 distance starting at 6.0 Å led to the complex II_H2O. Complex II_H2O: Mixed-Valence FeII(O2-)FeIII Superoxo Intermediate P*. Results presented in Table 1 indicate that the intermediate II_H2O is a mixed-valence species. In its ground 11A state, two Fe-centers have a different number of unpaired electrons. Fe2 to which the O2 molecule is coordinated in the end-on fashion is now “oxidized”, with roughly five unpaired electrons, and is in a high-spin ferric state, while Fe1 retains four unpaired electrons and remains in a ferrous state. Meantime, roughly one unpaired electron is shared by the O2-moiety, the spin of which is positioned parallel to spins of Fe-centers. The spin distribution, which is often a good measure of the valence
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TABLE 1: Mulliken Atomic Spin Densities (in e), O-O Bond Distance (r(O-O), in angstroms), and Selected Mulliken Charges (q, in e) for All the Stationary Points Involved in the Water-Assisted Reactiona structure I_H2O O2 II_H2O III_H2O IV_H2O V_H2O VI_H2O VII_H2O VIII a
2Ms+1
LnFe1 b
Fe2Ln
9 3 11 9 7 11 9 11 9 7 11 9 11 9 11 9 11 9
4.00
4.00
4.04 4.05 4.01 4.71 3.02 4.87 3.02 3.00 4.64 3.10 4.74 3.11 5.13 3.80 4.81 3.68
4.89 4.90 3.01 4.76 4.79 4.89 4.90 2.97 4.74 4.78 4.80 4.80 3.69 3.80 3.73 3.56
O1
O2
1.00 0.46 -0.36 -0.42 0.28 0.03 0.19 0.08 0.04 0.34 -0.01 0.18 -0.01 0.59 0.32 0.44 0.45
1.00 0.61 -0.59 -0.60 0.25 0.16 0.05 0.00 -0.01 0.28 0.13 0.29 0.10 0.59 0.08 1.04 0.31
oxidation state
r(O-O)
q(O1)
q(O2)
1.276 1.390 1.391 1.398 1.464 1.471 1.531 1.532 1.530 1.532 1.496 1.603 1.575 2.576 2.467 2.660 2.580
0.00 -0.22 -0.22 -0.22 -0.36 -0.24 -0.44 -0.43 -0.41 -0.24 -0.13 -0.24 -0.28 -0.27 -0.22 -0.19 -0.18
0.00 -0.31 -0.31 -0.27 -0.34 -0.34 -0.42 -0.38 -0.37 -0.33 -0.33 -0.30 -0.19 -0.32 -0.24 -0.24 -0.26
FeII FeII FeII(O2)-FeIII FeII(O2)-FeIII FeII(O2)-FeIII FeIII(O2)2-FeIII FeIII(O2)2-FeIII FeIII(O2)2-FeIII FeIII(O2)2-FeIII FeIII(O2)2-FeIII FeIII(O2)2-FeIII FeIII(O2)2-FeIII FeIII(O2)2-FeIII FeIII(O2)2-FeIII FeIII(O2-)2FeIV FeIV(O2-)2FeIV FeIII(O2-)2FeIV FeIV(O2-)2FeIV
Where LnFe1 and Fe2Ln are the sum over all ligands on Fe1 and Fe2, respectively. b For definitions of Fe1, Fe2, O1, and O2, see Figure 2.
state weakly coupled spin systems,23,25 indicates clearly that the intermediate II_H2O can be written as a mixed valence [FeII(O2-)FeIII] superoxo complex and was formed by oneelectron transfer from Fe2 to the O2 molecule. The Mulliken charge analysis in Table 1 shows that the O2-moiety has -0.54e charge, indicating substantial delocalization of the O2- negative charge in this neutral complex. As shown in Figure 3, the process I_H2O + O2 f II_H2O is calculated to be exothermic by 28.7 kcal/mol for the ground 11A state of II_H2O. To such a large stabilization energy, in addition to the formation of a strong Fe2-O1 bond, two H-bonds between the negatively charged O2 fragment and water hydrogens must be at least in part contributing. The 9A and 7A states of II_H2O are located by 3.9 and 13.0 kcal/mol higher in energy than the 11A state. Spin distribution in the 9A state is different from that in 11A only by direction of the spin located on the O2-moiety, which now is antiparallel to the Fe spins. As usual, this type of spin flip does not cause significant energy changes, which is consistent with the calculated small energy difference between 9A and 11A states. In the 7A state, in addition to the spin flip in the O2-fragment, two electrons of Fe2 center are paired, which made Fe2 a low-spin ferric iron. As usual, intraatomic spin coupling is an energy demanding process (that occurs with about 5-10 kcal/mol energy requirement for Fe-complexes), which is consistent with the calculated energy gap of 13.0 kcal/mol between 7A and 11A states. The calculated geometry parameters are consistent with the above given energy and spin distribution discussions. Indeed, the calculated O-O bond distances in II_H2O are 1.390-1.398 Å, which is close to that in the free O2- anion, 1.416 Å at the present level of calculations. On the basis of the above presented discussions, we believe that the intermediate II_H2O is the intermediate P* predicted by experimentalists.3 According to our best knowledge, this is the first time that the electronic structure of such an intermediate is reported. We also investigated an alternative structure for the intermediate II_H2O, called II′_H2O, not presented in Figure 2, with one monobridged carboxylate and with one bibridged. Optimization of structure II′_H2O converged to II_H2O. These calculations once again demonstrate that µ-1,2 (bidentate) bridging (bidentate) of the carboxylate ligands is preferred over their µ-1,1 (monodentate) bridging, at least within the current model.
Complexes III_H2O, IV_H2O, V_H2O, and VI_H2O: Intermediate P. In the next step of the reaction, the second electron transfer, this time from Fe1 to the O2-moiety, takes place, which leads to formation of [FeIII(O2)2-FeIII] type of species. We have found four intermediates, III_H2O, IV_H2O, V_H2O, and VI_H2O, corresponding to the [FeIII(O2)2-FeIII] complex, which are different only by coordination mode of the O2 molecule. Let us start our discussions from the isomer III_H2O. As seen in Figure 2, in the isomer III_H2O, the O2 molecule coordinates to the iron centers as a cis-µ-1,2 ligand (see Scheme 6). In the ground 11A state of III_H2O, the Fe-O bonds are roughly symmetric, 1.924 and 1.953 Å. The O-O bond distance in III_H2O is calculated to be 1.464 Å, which is 0.2 Å shorter than that in free O22- molecule, 1.665 Å, but is 0.07 Å longer than that in the superoxo complex II_H2O. As seen in Table 1, at the 11A ground state, isomer III_H2O is a high-spin diferric complex, [FeIII(O2)2-FeIII], with almost five unpaired electrons on each Fe-center and about 0.53e delocalized in the O2 moiety. However, in the 9A state, one of the iron centers, Fe1, becomes a low-spin ferric iron with three unpaired electrons. As usual, intraatomic spin coupling in this type of Fe-complexes is energetically unfavorable; the 9A state of III_H2O is 8.5 kcal/ mol higher than the 11A state. Recently, the crystal structures of three (biomimetic) binuclear peroxo [M(O2)2-M] complexes with cis-µ-1,2 bridging mode have been obtained.36 In these complexes the peroxide moiety has M-O-O-M dihedral angles ranging from 0° to 53°. The Fe-O-O bond angles are 120-129°, which are significantly larger than the Cu-O-O and Co-O-O angles in related µ-1,2peroxo [CuII(O2)2-CuII] and [CoIII(O2)2-CoIII] dimers (∼110°).37 In the ground 11A state of III_H2O, the Fe-O-O-Fe dihedral angle is calculated to be 10°, and the Fe-O-O angles are 129° and 134°, which are in fairly good agreement with available experimental data presented above. In the isomer IV_H2O, which also has the 11A ground state, the O2 molecule is coordinated to the iron centers as an end-on µ-1,1 ligand. The Fe-O1 bonds are calculated to be 2.037 and 2.076 Å, which are about 0.1 Å longer than those in isomer III_H2O. Meantime, the O-O bond distance, 1.531 Å, is also larger than that in III_H2O, 1.464 Å. This must be mainly due to less delocalization of the O22- negative charge to irons and less delocalization of iron spins to the O2-moiety; the O2-moiety
4460 J. Phys. Chem. B, Vol. 105, No. 19, 2001 in IV_H2O is more O22--like than that in III_H2O. The existence of relatively strong hydrogen bonds between distal oxygen atom O2 of the O2-moiety and water ligands may also contribute to this situation. These geometry differences of the isomers III_H2O and IV_H2O well correlate with the energy differences of these complexes; III_H2O with less activated O-O bond is calculated to be about 23 kcal/mol higher in energy than IV_H2O. Table 1 shows that in the 11A state, IV_H2O is a high-spin FeIII-FeIII species, with approximately five spins per iron center (4.87e on Fe1 and 4.89e on Fe2) and some spin delocalized into the two oxygen atoms (0.19e and 0.05e on O1 and O1, respectively). However, the 9A state of the IV_H2O has an unfavorable low-spin ferric center, Fe1, with three spins (3.02e) and a high-spin ferric center, Fe2, with five spins (4.90e), and lies 6.5 kcal/mol above 11A. Its 7A state having two unfavorable low-spin ferric centers with three spins on each irons (3.00e and 2.97e on Fe1 and Fe2, respectively) lies even higher, 17.2 kcal/mol, than 11A. In the third isomer, V_H2O, the O2 ligand is positioned between two Fe atoms forms a distorted trans-µ-1,2 mode (see Scheme 6) of bridge, and it is bound asymmetrically to Fecenters with two short and two long Fe-O bonds. The O-O bond distance (for 11A state) is found to be 1.532 Å, which is very close to that for isomer IV_H2O. The most stable electronic state of the isomer V_H2O is 11A, the same most stable electronic state as in the isomers III_H2O and IV_H2O, and has two high-spin ferric centers with approximately five spins on each iron center (4.64e and 4.74e, for the Fe1 and Fe2, respectively). A large (0.62e) delocalization of spin into the two oxygen atoms takes place. Its 9A state lies 13.8 kcal/mol higher than 11A mainly due to the unfavorable spin coupling in the low-spin ferric Fe1. In the respective ground state (11A), isomer V_H2O is found to be 10.2 kcal/mol lower than III_H2O, but 12.7 kcal/mol higher than IV_H2O. Recently, Siegbahn has reported21 the asymmetric peroxo [FeIII(O2)2-FeIII] complex, which is similar to isomer V_H2O. In the fourth isomer, VI_H2O, the O2 ligand coordinated to the Fe-centers via roughly µ-η2,η2 manner, where there are four Fe-O bonds, and the O-O distance is calculated to be 1.575 and 1.603 Å for the 9A and 11A states, respectively (see Figure 2). In other words, in the VI_H2O complex, the O-O distance has elongated by 0.07-0.08 Å compared with that in V_H2O, but it is short by 1.0-0.9 Å compared to that on the complex VII_H2O. Therefore, VI_H2O is expected to be located between the complexes V_H2O and VII_H2O. Another interesting feature of complex VI_H2O is its bent “butterfly” character, with a hinged O-O axis. The calculated Fe-Fe-O-O dihedral angle is 32.1° and 35.4°for the 9A and 11A states, respectively. The origin of the bend is electronic in nature, i.e., due to more extensive opportunities for orbital mixing between the 3d-orbitals of Fe’s and the σ, σ*, π, and π* orbitals of the molecular oxygen, facilitated by interaction of the carboxylate ligand with a water molecule. The frequency calculations confirmed the nature of the complex VI_H2O, which has no imaginary frequency and is a real minimum on the potential energy surface. The structure with a planar Fe2O2 subunit, VII_H2O, lies by several kcal/mol lower than complex VI_H2O and separated from it with an energetic barrier, the search for which is in progress. Below, we will discuss complex VII_H2O in more detail. As seen in Table 1, for the ground 11A state, the VI_H2O complex has two high-spin ferric (with roughly five unpaired electrons) centers, while in the excited 9A state one of the Fe’s becomes low-spin ferric. Isomer VI_H2O is found to be 8.3
Torrent et al. and 7.3 kcal/mol higher than isomer V_H2O for the 11A and 9A states, respectively. Interestingly, comparison of the structures of the isomers III_H2O, IV_H2O, V_H2O, and VI_H2O with that of complex II_H2O, which can be considered as a pre-reaction complex for formation of the former, shows that the second electrontransfer process (from the Fe1 center) is accompanied by the dissociation of one of Fe1-O (carboxylate) bonds and formation of Fe1-HOH‚‚‚OCHO-Fe2 network. In other words, during this process, one of µ-1,2-bridged carboxylates raises one of its “legs” while forming a new hydrogen bond with the water ligand, and creates a “coordinatively unsaturated” Fe1 center to facilitate the attack of the O2-moiety. Thus, a water molecule in the active site of the MMOHred facilitates the formation of intermediate P (the complexes III_H2O, IV_H2O, V_H2O, and VI_H2O, in the present paper), and O-O bond activation. Thus, we have located four different minima, III_H2O, IV_H2O, V_H2O, and VI_H2O, corresponding to the peroxo [FeIII(O2)2-FeIII] complex (which experimentalists call an intermediate P) using the present model. As summarized in Figure 3, the stability (relative to the I_H2O + O2 dissociation limit) of these isomers increases in the order: III_H2O (34.5 kcal/mol) < VI_H2O (36.4 kcal/mol) < V_H2O (44.7 kcal/ mol) < IV_H2O (57.4 kcal/mol). On the basis of the structural analysis and calculated O-O bond distances, one may expect that isomers III_H2O, V_H2O and VI_H2O are intermediates on the potential energy surface of the homolytic O-O activation reaction, while isomers III_H2O and IV_H2O are intermediates of the heterolytic O-O activation reaction. Since all of them are minima on the potential energy surface, one should expect the existence of energetic barriers between these isomers, i.e., between III_H2O and IV_H2O, III_H2O, and V_H2O, and V_H2O and VI_H2O. At this moment we have not calculated these transition states, and do not know the barrier heights separating these isomers, while these barriers could be crucial in determining the mechanism of the O-O bond activation by MMOHred. Indeed, if the barrier corresponding to the III_H2O f IV_H2O process is smaller than that for the III_H2O f V_H2O, then complex III_H2O will rearrange into complex IV_H2O and, consequently, the O-O activation process will proceed via the heterolytic O-O activation pathway. On the contrary, if the barrier for the III_H2O f IV_H2O is larger than that for III_H2O f V_H2O, then complex III_H2O will rearrange into complex V_H2O, and the process is likely to proceed by the homolytic O-O activation mechanism. One expects that the energetic barrier for the III_H2O f IV_H2O is smaller for the following reasons. (1) The reaction III_H2O f IV_H2O is highly, 23 kcal/mol, exothermic, and therefore, the transition state of this process is expected to be very early, and (2) the III_H2O f IV_H2O isomerization process does not involve any dramatic structure and spin state changes. Meantime, the barrier for III_H2O f V_H2O, as well as that for IV_H2O f V_H2O, could be relatively high. These discussions are premature and need more calculations (currently in progress). Note that the coordination of the oxygen molecule to the binuclear non-heme iron oxygen-activating enzymes, as well as the corresponding biomimetic models, has been the subject of extensive studies.3,38 These studies have demonstrated several possible isomers for the peroxide intermediates (see Scheme 6), and unveiled similarities in their structures and electronic features. For example, their electronic absorption spectra show an intense broad band centered around 600-750 nm, assigned to a peroxide-to-FeIII charge-transfer transition. Mo¨ssbauer,
Nonheme Iron Complexes isotopic labeling and spectroscopic studies of different enzymes and biomimetic complexes of (O2)-[FeIII] type suggested a cisµ-1,2 coordination mode of the dioxygen molecule in intermediate P. However, we expect that µ-η2-η2 and µ-1,1 coordination modes are the critical structures on the way to homolytic and heterolytic O-O activation processes, respectively, both leading to intermediate Q. In previous theoretical studies, several different structures were assigned for intermediate P: (1) end-on cis-µ-1,2-peroxo and side-on µ-η2:η2-peroxo structures were predicted by Yoshizawa and co-workers,39,18 while Siegbahn21 predicted a distorted trans-µ-1,2-peroxo structure (with an additional weak interaction between the peroxo ligand and one of the iron centers). Complexes VII_H2O and VIII: Intermediate Q. As mentioned above, further elongation of the O-O bond (by approximately 1.0 Å from VI_H2O to VII_H2O, Figure 2) and “planarization” of the Fe2O2 fragment lead to the formation of complex VII_H2O. As seen in Table 1, complex VII_H2O in the ground 9A state has two ferryl FeIV centers with about 3.80 unpaired electrons on each Fe, and about 0.40e electron delocalized on the O2-moiety, which is in excellent agreement with available experimental data40 indicating two FeIV centers for intermediate Q. The 11A state with one ferryl (Fe2) and one high-spin ferric (Fe1) centers is calculated to be 9 kcal/mol higher in energy. Another feature of the calculated complex VII_H2O, two long (Fe1-O ) 1.900 Å and Fe2-O ) 1.967 Å) and two short (Fe1-O ) 1.758 Å and Fe2-O ) 1.804 Å) Fe-oxo bonds, is also an excellent agreement with available experimental results for the FeIV2(µ-O)2 diamond core; EXAFS data show that the FeIV2(µ-O)2 diamond core of intermediate Q has two short Fe-O (1.77 Å) and two long Fe-O bonds (2.05 Å). However, the calculated Fe-Fe distance, 2.758 Å, is about 0.30 Å larger than its experimental value, 2.46 Å.40 This discrepancy could be the result of assuming ferromagnetic coupling in our calculations (vs antiferromagnetic experimentally), together with the existence of an additional water molecule in the system. Thus, complex VI_H2O could be labeled as a [FeIV(O2-)2FeIV] complex. As seen in Figure 3, the ground electronic state of complex VI_H2O is 11A, and the 9A state lies 12.8 kcal/mol higher. However, the ground state of VII_H2O is 9A state, and its 11A state lies 9.0 kcal/mol higher. In other words, one should expect spin crossing between 11A and 9A states upon going from complex VI_H2O to complex VII_H2O. Studies of the transition state connecting VI_H2O to VII_H2O, which corresponds to the O-O activation process, are in progress. Dissociation of the water molecule from the complex VII_H2O leading to the formation of complex Q, structure VIII, is energetically unfavorable by 24 kcal/mol. However, one should mention that the exact nature of intermediate Q still needs to be clarified. Indeed, although experiments40 have been able to characterize Q as an asymmetric FeIV2(µ-O)2 diamond core structure, the positions and nature of the remaining ligands are not known. Whether the two iron centers are bridged by one, two or more carboxylate ligands is still a topic of current debate,41 and our studies of this problem are in progress. Here we propose intermediate Q to have a structure like either VII_H2O or VIII. V. Comparison of “Water-free” and “Water-assisted” Mechanisms Comparison of the relative energies of the calculated intermediates (Figures 1 and 3) of reaction 3 for the “water-free”
J. Phys. Chem. B, Vol. 105, No. 19, 2001 4461 and “water-assisted” models, I and I_H2O, respectively, and their structures unveils several distinctive differences. First, adding an extra water ligand significantly (by 10-15 kcal/mol) stabilizes the diferric peroxo [FeIII(O2)2-FeIII] complexes, III_H2O, IV_H2O, and V_H2O (for the “water-free” model we were not able to locate “butterfly” structure VI_H2O, see below). As a result, all isomers of the diferric peroxo [FeIII(O2)2-FeIII] complex lie lower in energy than the mixedvalence superoxo [FeII(O2)-FeIII] complex, II_H2O, in the “water-assisted” model studies. Consequently, one could expect the “water-assisted” conversion of the superoxo intermediate into the peroxo diferric complex is going to be much easier than that for the “water-free” one. In other words, the additional water molecule around the active site of MMOHred facilitates the superoxo f peroxo conversion. This could be explained by close examination of the structures of these complexes. Having an additional water ligand did not significantly change the structures of the superoxo complexes (structures II and II_H2O). However, it significantly changes the structures of the peroxo complexes; in the “water-assisted” complexes III_H2O, IV_H2O, V_H2O, and VI_H2O the second electron transfer (from Fe1 center) accompanies the dissociation of one of the Fe1-O(carboxylate) bonds and formation of Fe1-HOH‚‚ ‚OCHO-Fe2 network. In summary, for the “water-assisted” mechanism, the superoxo f peroxo conversion process is accompanied by “raising one of the legs” of one of the µ-1,2bridged carboxylates and forming the hydrogen bond with the water ligand. The “extra coordination site” gained by these geometrical changes facilitates the approach of the O2-moiety to the Fe-centers and the formation of intermediate P (complexes III_H2O, IV_H2O, and V_H2O). Second, we have located an additional isomer, “butterfly” complex VI_H2O, for the “water-assisted” model. A similar complex for the “water-free” model studies was not located. We believe the stabilization of the “butterfly” complex VI_H2O is the result of the existence of an Fe1-HOH‚‚‚OCHO-Fe2 network. Indeed, having an additional water molecule on Fe1, which evolves into HOH‚‚‚OCHO-Fe2 type of interaction, is expected to increase the weights of the Fe 3d-orbitals in the Fe-O2-Fe interaction leading to formation of the “butterfly” type of structure. Third, the process I_H2O + O2(3Σ) f VII_H2O is calculated to be 17.5 kcal/mol more exothermic than the similar process in “water-free” reaction, I + O2(3Σ) f VII. VI. Conclusions From the above results one may draw the following conclusions. 1. The “water-assisted” homolytic O-O bond activation by MMOHred, reaction 3, proceeds via (i) the coordination of the dioxygen molecule to one of the Fe atoms of the complex I_H2O leading to formation of the mixed-valence superoxo complex, [FeII(O2)-FeIII], II_H2O; (ii) the second electron transfer from the Fe atom to the O2-moiety to form the cis-µ-1,2 peroxo complex [FeIII(O2)2-FeIII], III_H2O; (iii) the conversion of the cis-µ-1,2 isomer, III_H2O, to the distorted trans-µ-1,2 isomer, V_H2O; (iv) the conversion of the distorted trans-µ-1,2 isomer, V_H2O, to the “butterfly” type of µ-η2-η2 complex VI_H2O; (v) activation of the O-O bond; and (iv) formation of the diferryl complex [FeIV(µ-O)2FeIV] complex via spin flip. 2.The peroxo complex [FeIII(O2)2-FeIII] is found to have four different isomers, III_H2O, IV_H2O, V_H2O, and VI_H2O, corresponding to the cis-µ-1,2, end-on µ-1,1, distorted transµ-1,2, and µ-η2-η2 coordination modes of the O2 molecule. The
4462 J. Phys. Chem. B, Vol. 105, No. 19, 2001 conversion of the cis-µ-1,2 isomer, III_H2O, to the distorted trans-µ-1,2 isomer, V_H2O, is the first step of the homolytic O-O activation process, while the conversion of the cis-µ-1,2 isomer, III_H2O, to the end-on µ-1,1 isomer, V_H2O, is expected to be the first step of the heterolytic O-O activation process, the studies of which are in progress. Complex VI_H2O with the µ-η2-η2 coordination modes of the O2 molecule is believed to be located between the distorted trans-µ-1,2 isomer V_H2O and compound Q, VII_H2O, with broken O-O bond and two ferryl Fe-centers. 3. Having an additional water molecule around the active site of MMOHred facilitates the superoxo f peroxo conversion process because of opening one of the “legs” of µ-1,2-bridged carboxylate accompanied by formation of Fe1-HOH‚‚‚OCHOFe2 network. Acknowledgment. The present research is in part supported by a grant (CHE96-27775) from the National Science Foundation. M.T. gratefully acknowledges a Postdoctoral Fellowship from the Spanish Ministerio de Educacio´ n y Cultura. Acknowledgment is made to the Cherry L. Emerson Center of Emory University for the use of its resources, which is in part supported by a National Science Foundation grant (CHE-0079627) and an IBM Shared University Research Award. Acknowledgment is also made for the computer time allocated at the Center for Supercomputing Applications (NCSA). Supporting Information Available: Cartesian coordinates and 〈S2〉 values of all intermediates. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Valentine, J. S., Foote, C. S., Greenberg, A., Liebman, J. F., Eds. In ActiVe Oxygen in Biochemistry; Chapman and Hall: London, 1995. (2) Ortiz de Montellano, P. R., Ed. Cytochrome P450: Structure, Mechanism, and Biochemistry, 2nd ed.; Plenum Press: New York, 1995. (b) Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem. ReV. 1996, 96, 2841. (3) Stenkamp, R. E. Chem. ReV. 1994, 94, 715. (b) Feig, A. L.; Lippard, S. J. Chem. ReV. 1994, 94, 759. (c) Wallar, B. J.; Lipscomb, J. D. Chem. ReV. 1996, 96, 2625. (d) Solomon, E. I.; Brunold, T. C.; Davis, M. I.; Kemsley, J. N.; Lee, S.-K.; Lehnert, N.; Neese, F.; Skulan, A. J.; Yang, Y.-S.; Zhou, J. Chem. ReV. 2000, 100, 235 and references therein. (e) MacBeth, C. E.; Golombek, A. P.; Young, V. G., Jr.; Yang, C.; Kuczera, K.; Hendrich, M. P.; Borovik, A. S. Science 2000, 289, 938. (4) DeRose, V. J.; Liu, K. E.; Kurtz Jr., D. M.; Hoffman, B. M.; Lippard, S. J.; J. Am. Chem. Soc. 1993, 115, 6440. (b) Fox, B. G.; Hendrich, M. P.; Surerus, K. K.; Andersson, K. K.; Froland, W. A.; Lipscomb, J. D. J. Am. Chem. Soc. 1993, 115, 3688. (c) Thomann, H.; Bernardo, M.; McCormick, J. M.; Pulver, S.; Andersson, K. K.; Lipscomb, J. D.; Solomon, E. I. J. Am. Chem. Soc. 1993, 115, 8881. (5) Rosenzweig, A. C.; Fredrick, C. A.; Lippard, S. J.; Nordlung, P. Nature 1993, 366, 537. (b) Rosenzweig, A. C.; Nordling, P.; Takahara, P. M.; Fredrick, C. A.; Lippard, S. J. Chem. Biol. 1995, 2, 409. (6) Elango, N.; Radhakrishman, R.; Froland, W. A.; Waller, B. J.; Earhart, C. A.; Lipscomb, J. D.; Ohlendorf, D. H.; Protein Sci. 1997, 6, 556. (b) Nesheim, J. C.; Lipscomb, J. D. Biochemistry, 1996, 35, 10240 and references therein. (7) See ref 1 and references therein. (b) Stubbe, J.; J. Biol. Chem. 1990, 265, 5329. (b) Sjoberg, B.-M.; Graslund, A. AdV. Inorg. Biochem. 1983, 5, 87. (c) Reichard, P.; Ehrenberg, A. Science, 1983, 221, 514. (8) See ref 1 and references therein. (b) Reinchard, P. Science 1993, 260, 1773. (c) Stubbe, J.; van der Donk, W. A. Chem. ReV. 1998, 98, 705. (d) Mulliez, E.; Fontecave, M. Coord. Chem. ReV. 1999, 185-186, 775. (e) Nordlund, P.; Sjoberg, B.-M.; Eklund, H. Nature, 1990, 45, 593. (9) See ref 3 and references therein. (10) Logan, D. T.; Su, X.-D.; Åberg, A.; Regnstro¨m, K.; Hajdu, J.; Eklund, H.; Nordlund, P. Structure 1996, 4, 1053-1064. (11) See ref 1 and references therein. (b) Rosenzweig, A. C.; Frederick, C. A.; Lippard, S. J.; Nordlund, P. Nature 1993, 366, 537-543. (c) Rosenzweig, A. C.; Nordlund, P.; Takahara, P. M.; Frederick, C. A.; Lippard, S. J. Chem. Biol. 1995, 2, 409-418. (12) Pulver, S. C.; Froland, W. A.; Lipscomb, J. D.; Solomon, E. I. J. Am. Chem. Soc. 1997, 119, 387-395.
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