Missing Pieces in the Puzzle of Biological Water Oxidation - ACS

Review Cite This: ACS Catal. 2018, 8, 9477−9507

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Missing Pieces in the Puzzle of Biological Water Oxidation Dimitrios A. Pantazis*

ACS Catal. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/18/18. For personal use only.

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany ABSTRACT: The sunlight-powered oxidation of water by photosystem II (PSII) of algae, plants, and cyanobacteria underpins the energy conversion processes that sustain most life on our planet. Understanding the structure and function of the “engine of life”, the oxygen-evolving complex (OEC) in the active site of PSII, has been one of the great and persistent challenges of modern science. Immense progress has been achieved in recent years through combined contributions of diverse disciplines and research approaches, yet the challenge remains. The improved understanding of the tetramanganese−calcium cluster of the OEC for the experimentally accessible catalytic states often creates a more complex picture of the system than previously imagined, while the various strands of evidence cannot always be unified into a coherent model. This review focuses on selected current problems that relate to structural−electronic features of the OEC, emphasizing conceptual aspects and highlighting topics of structure and function that remain uncertain or controversial. The Mn4CaOx cluster of the OEC cycles through five redox states (S0−S4) to store the oxidizing equivalents required for the final step of dioxygen evolution in the spontaneously decaying S4 state. Remarkably, even the dark-stable state of the OEC, the S1 state, is still incompletely understood because the available structural models do not fully explain the complexity revealed by spectroscopic investigations. In addition to the nature of the dioxygen-evolving S4 state and the precise mechanism of O−O bond formation, major current open questions include the type and role of structural heterogeneity in various intermediate states of the OEC, the sequence of events in the highly complex S2−S3 transition, the heterogeneous nature of the S3 state, the accessibility of substrate or substrate analogues, the identification of substrate oxygen atoms, and the role of the protein matrix in mediating proton removal and substrate delivery. These open questions and their implications for understanding the principles of catalytic control in the OEC must be convincingly addressed before biological water oxidation can be understood in its full complexity on both the atomic and systemic levels. KEYWORDS: photosynthesis, photosystem II, water oxidation, oxygen evolution, manganese, catalysis

1. INTRODUCTION What is most remarkable about the oxygen-evolving complex (OEC) of photosystem II (PSII) is not that it oxidizes water but how it does so.1−4 Available observations suggest highly efficient control mechanisms that enable effective four-electron chemistry, avoidance of early onset of oxidation reactions, elimination of side reactions, and low-barrier and practically irreversible formation and/or release of dioxygen in the final catalytic step. Synthetic molecular and heterogeneous manganese analogues still struggle to mimic the function and performance of the OEC.5−7 This is partly because these distinctive features are not intrinsic to the Mn4CaOx core of the OEC but depend on its environment and result from elaborate gating and regulation mechanisms for coordinating the coupling of proton−electron transfer and the access, delivery, binding, positioning, activation, and coupling of substrate waters to form dioxygen. The high level of geometric and electronic control, both spatial and temporal, extends along the whole catalytic cycle and involves simultaneously the Mn4CaOx cluster, its first coordination sphere, and the protein matrix that controls the flow of electrons, protons, substrates, and products. The three layers combine to create a complex © XXXX American Chemical Society

entity that can only be properly understood as a system. It would therefore be lamentable to reduce the discussion on the “mechanism of biological water oxidation” to the hypothetical features of a single putative transition state for O−O bond formation. This still unknown step is definitely important but represents only one piece of a much bigger puzzle. Research on biological water oxidation traverses scientific fields and concentrates the efforts of a multitude of experimental and theoretical approaches. Different methods of investigation naturally lead to distinct views on the OEC. These are often complementary but at times are contradictory, and it is not always obvious whether the contradictions already exist in the data or arise from their suggested interpretations. Nevertheless, the overarching goals are common to all experimental and theoretical studies. These are not limited to the geometric and electronic structure of the cluster in each state of the cycle but encompass the role of the protein matrix, the channels, and secondary components of the second sphere Received: May 18, 2018 Revised: August 23, 2018 Published: September 4, 2018 9477

DOI: 10.1021/acscatal.8b01928 ACS Catal. 2018, 8, 9477−9507

Review

ACS Catalysis

radical cation P680•+, which is stabilized as the electron is localized first at the pheophytin PheoD1 and then at the primary plastoquinone acceptor, PQA. The electron is transferred through a non-heme Fe site to the final acceptor plastoquinone, PQB, that is eventually released as PQH2 to carry the reducing equivalents along the photosynthetic chain that includes cytochrome b6 f and photosystem I. Wider perspectives on the overall function of PSII and the regulatory roles of the various electron transfer mechanisms are discussed elsewhere.9,10 Focusing on the donor side of PSII, the electron hole at P680•+ is filled by oxidation of a redoxactive tyrosine residue of the D1 protein, Tyr161 or YZ. Formation of the YZ• radical is facilitated by proton transfer to the hydrogen-bonded histidine residue His190. Tyr161 interacts closely with the manganese cluster of the OEC, and hence, YZ• plays the role of its immediate oxidant. The heart of the OEC consists of an inorganic cluster composed of four manganese ions and one calcium ion bridged by oxo or hydroxo ligands (Mn4CaOx). The cluster is coordinated by carboxylate residues (Asp and Glu) and one histidine and also ligates four terminal H2O or OH ligands. The structure of the cluster will be discussed in greater detail in the following sections. In terms of a broad description of its function, the OEC can be seen as a bioinorganic device that combines the role of an accumulator of electron holes with that of an oxygen-evolving catalyst. The YZ• radical oxidizes the Mn4CaOx cluster of the OEC in one-electron steps. Four such oxidations take place before dioxygen evolution is observed, demonstrating that four oxidizing equivalents are stored at the OEC before they are used in O−O bond formation. This progression is described by the Joliot−Kok cycle of Si states (Figure 2),11,12 where i can

of the cluster, such as the chloride ions. The present review primarily focuses on the structural heterogeneity of the OEC in individual catalytic states, the water channels, and the events that take place in the S2−S3 transition as well as the nature of the last observable state (S3) and the possible progressions to the O−O bond formation step, with the aim of highlighting major open questions that are critical for understanding the function of this unique biological system in all of its intricate and highly orchestrated complexity.

2. PHOTOSYSTEM II AND THE OXYGEN-EVOLVING COMPLEX As the first member in the membrane-embedded enzymatic relay system of oxygenic photosynthesis, dimeric PSII catalyzes the transfer of electrons from water to a mobile plastoquinone (PQ). Specifically, the enzyme couples the four-electron water oxidation to dioxygen on the donor side (eq 1) to the twoelectron plastoquinone reduction on the acceptor side (eq 2), 2H 2O → O2 + 4H+ + 4e−

(1)

PQ + 2e− + 2H+ → PQH 2

(2)

driving both processes with a light-induced one-electron charge separation originating at a set of chlorophyll molecules termed the primary electron donor (or reaction center). At the same time, it generates a membrane proton gradient that drives ATP synthase. The major redox-active components that participate in electron transfer are distributed mostly in the D1 and D2 proteins of PSII in a quasi-symmetric arrangement, as depicted in Figure 1. The light-driven charge separation at the reaction center generates one of the strongest oxidants in biology, the

Figure 2. OEC cycle of five oxidation states Si (i = 0−4). Also shown are the YZ radical intermediates, which can be trapped and yield important information on the properties of the metal cluster and the mechanism of each transition.

take integer values from 0 to 4: S0 is thus the most reduced state of the cycle and S4 the most oxidized state, which evolves dioxygen. S1, called the “dark-stable” state, is the state to which most of the OEC centers in a PSII sample revert if left in the dark. With the exception of the S4 state (and mostly everything that occurs after formation of the S3YZ• intermediate and the reconstitution of S0), all of the other states are observable and have been the subject of experimental studies. The localization of oxidation events, that is, whether they are Mn-centered and whether they are localized on individual Mn ions in each transition, has been a long-standing problem in photosynthesis research. Today it is widely accepted that at

Figure 1. (a) Photosystem II is a dimeric membrane protein−cofactor complex. Each PSII monomer consists of more than 20 proteins and exhibits a pseudodimeric arrangement. Coordinates were obtained from reference 8. (b) Major pigments, redox-active cofactors, and other important residues involved in charge separation, electron transfer, and catalysis. The orange arrows indicate the physiological electron flow from the donor side to the acceptor side. 9478


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ACS Catalysis least the first three oxidations involve individual Mn ions, a notion that has strong support from electron paramagnetic resonance (EPR)13 and X-ray spectroscopy data. 14−19 However, alternative interpretations are still being discussed that require the S 3 state to involve ligand-centered oxidation.20,21 This point has become more contentious with the advent of preliminary models of the S3 state obtained by Xray free electron laser (XFEL) X-ray diffraction (XRD) studies,22,23 which are, however, inconsistent with the available electronic structure information on this state. Moreover, contrasting pictures of the locality of oxidation events are obtained by different methods, with some interpretations of resonant inelastic X-ray scattering spectroscopy (RIXS) suggesting that the electron in each transition is removed from highly delocalized orbitals with significant ligand participation,24,25 whereas EPR and computational studies typically describe the Si−Si+1 transitions as oxidation events that are highly localized on specific individual Mn ions. Since the nature of the S3 state is still contentious and there is hardly any information on the events intermediate between the S3YZ• and S0 states, it also not clear whether the “charging” phase consists of four genuine metal-centered oxidationsor indeed whether this distinction can be made at all in the final steps of the cycle. A rather safe assignment concerns the alternating nature of electron/proton removal,26,27 which is consistent with a 1:0:1:2 proton release pattern for each transition,27 as indicated in Figure 2. This is well-supported by time-resolved photothermal beam deflection experiments, which have identified relevant transient intermediates in the S0−S1 and S2−S3 transitions.28,29 On the other hand, the precise points of water insertion along the cycle remain ill-defined. Although at least one water binding event must occur upon reconstitution of the S0 state after dioxygen release, it is still unclear whether the other occurs before, during, or after the S2−S3 transition. A large part of OEC research can be simply summarized with the questions of what are the geometric and electronic structures of the Si states, how do they transform from one to the next, and what is the role of the protein in enabling these transitions and facilitating the chemistry of water oxidation. As will be discussed in the following, we have come a long way toward answering these questions, but we are not quite there yet. In the following, the structure of the S1 state will be discussed first, as this is the dark-stable state of the enzyme and hence has been the focus of most structural investigations to date. Subsequently the properties of the two neighboring states, S0 and S2, will be discussed. The transition from the S2 state to the S3 state is highly complex and forms one of the current frontiers in OEC research. Before this transition is discussed, it is necessary to describe the channels relevant to the OEC as well as some insights gained from the interaction of small molecules with the cofactor. Finally, aspects of the S3 state will be described along with hypotheses regarding advancement to the S4 state and O−O bond formation.

distances and possible three-dimensional arrangements. Contributions from EXAFS have been reviewed elsewhere16,30−34 and will not be revisited here. Low-resolution crystallographic models of PSII appeared only in 2001.35 The 3.5 Å resolution model published in 2004 by Ferreira et al.36 was the first to propose a specific arrangement of not only the Mn and Ca ions but also of oxygen bridges.36,37 This model suggested a stoichiometry of Mn4CaO4 for the inorganic core, with a structure involving a Mn3CaO4 cubane to which a “dangling” Mn ion is attached through a μ4-O bridge. The Yshaped arrangement of the Mn ions had been proposed earlier from EPR studies.38 In combination with the further refined view of the ligand sphere by a subsequent 3.0 Å resolution structure,39 this model led to a revision of previously proposed topologies40 and encouraged structurally informed computational studies on the OEC and its catalytic cycle. In this respect, two major lines of work have been pursued by the groups of Batista41,42 and Siegbahn,43 who proposed models that deviated to different extents from crystallography. These formed the basis of entire mechanistic schemes44,45 that had to be either abandoned or modified after more recent crystallographic advances.8 A distinct line of research emphasized the use of EXAFS data in constructing three-dimensional models of the OEC. An important contribution involved polarized EXAFS on single crystals of PSII,46 which led to several suggestions regarding the arrangements of Mn and Ca ions.46,47 The polarized EXAFS models were hard to reconcile with the ligand environment and, as shown by quantum-chemical analysis,48 were broadly incompatible with the magnetism and spectroscopy of the OEC.49 Interestingly, Ames et al.50 demonstrated that one of the models proposed from polarized EXAFS on single crystals of PSII46 was an approximate mirror image of the later crystallographic model of Umena et al.,8 suggesting a potential phase issue in the original analysis. On the other hand, Dau and Haumann30,51,52 combined the ligand assignment of Loll et al.39 with extended-range EXAFS data to suggest a different structural model with five oxo bridges and a tentative topological assignment of individual Mn oxidation states. Our present structural understanding of the OEC was decisively shaped by the 2011 XRD model of PSII from Thermosynechococcus vulcanus by Umena et al.8 at a resolution of 1.9 Å (Figure 3). This was not a drastic departure from previous models in all respects but immediately disqualified a number of hypotheses and EXAFS interpretations, clarifying assignments regarding the number and connectivity of oxygen bridges and the coordination and orientation of amino acid side chains. Significantly, the core of the model (Mn4CaO5) differs in oxygen bridge stoichiometry from the Ferreira et al. XRD model and all of the computational models proposed before 2011 but matches the Dau−Haumann model in both stoichiometry and overall topology.51,52 For an extended discussion of structural comparisons and an analysis of EXAFS in relation to crystallography, we refer the reader to the excellent review by Grundmeier and Dau.30 Differences in the number and type of oxo bridges between models may appear minor but are crucial for interpreting observable properties of catalytic intermediates. For example, a closed Mn3CaO4 cubane subunit53,54 would be incompatible55,56 with the low-spin ground states of the cluster in the three lowest Si states.

3. THE DARK-STABLE S1 STATE 3.1. Structural Refinement and Uncertainties. As the dark-stable resting state of PSII, the S1 state is the primary target of structural methods such as extended X-ray absorption fine structure spectroscopy (EXAFS) and protein crystallography. EXAFS holds a prominent place in the history of structural studies because for a long time it was the only source of direct structural information in the form of metal−metal 9479


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Asp61, which interacts with the W1 ligand; and CP43-Arg357, which may interact with O4, Asp170, and possibly other residues because of the flexibility of the guanidinium. A functionally required chloride ion57,58 is located close to the OEC and interacts with first-sphere residues via hydrogen bonding, possibly with the involvement of D2-Lys317, while the redox-active tyrosine D1-Tyr161 (YZ) interacts directly with one of the Ca-bound water molecules (W4). According to later computational studies that used the Umena et al. model as the point of departure for the study of the EPR properties of the S2 state50 (which should have the same protonation state as S1; see Figure 2) and for estimation of pKa values,59 the most likely arrangement of protons requires all of the bridges to be deprotonated (oxo) and all of the terminal water-derived ligands to be present as neutral H2O molecules, with the exception of W2, which is most likely present as a hydroxide. This assignment best reproduces the observed55Mn hyperfine coupling constants from electron− nucleus double resonance (ENDOR) spectroscopy38,60 of the S2 state.50,56 Currently there is consensus regarding the protonation states of the bridges, but several studies instead favor all four terminal water-derived ligands to be present as H2O in the S1 state on the basis of either EXAFS simulations,61 vibrational spectroscopy calculations,62 or the effect on computationally optimized structures.63 This alternative assignment does not necessarily spoil the magnetic properties, since both the S1 and S2 states are predicted to retain their lowspin ground states (S = 0 for the S1 state and S = 1/2 for the major form of the S2 state) either with W1 = W2 = H2O or with W1 = H2O and W2 = OH.56 Hence, it is not straightforward to make a safe distinction between the two possibilities on the basis of predicted EPR parameters, which to date have proven to be highly discriminative in the context of quantum-chemical modeling. Although not critical for interpreting most of the properties of the S1 and S2 states themselves, this detail is not trivial because the total protonation state of the dark-stable state has important implications for the details of the crucial S2−S3 transition and hence for the structure of the S3 state. Although the atomic-resolution model of 2011 unquestionably redefined the structural reference point for subsequent studies, certain problematic aspects were apparent.30,50 The metal−oxygen bond lengths in the core (ca. 2.2 Å on average; see Figure 4b) were incompatible with EXAFS (ca. 1.85 Å) and outside the distribution of Mn−O/N bond lengths observed in synthetic manganese complexes with oxidation states similar to those of the OEC.64 Additionally, the O5 bridge was situated at nonbonding distances from every metal atom, and the short Mn−Mn distances of the crystallographic model (ca. 2.8, 2.9, and 3.0 Å) were too long to be consistent with the distances obtained by EXAFS (two at 2.65−2.8 Å and possibly a third at 2.7−2.8 Å).30,50,65 The Mn oxidation states in the dark-stable state of the OEC are Mn(III)2Mn(IV)2, but a bond-valence sum analysis of the Umena et al. structure leads to Mn oxidation states for the Mn1−Mn4 ions of +2.8, +2.7, +2.5, and +2.1, which are more consistent with oxidation state assignments of III−III−II−II (formally, a nonphysiological “S−3”) state.30 In a similar vein, a detailed computational study led to the conclusion that the experimental structure was a mixture of states with a dominant contribution (ca. 60%) of such a Mn(II)2Mn(III)2 species.65 On the basis of QM/MM simulations coupled to simulations of EXAFS spectra, it was also concluded that the 2011 XRD model corresponds to a

Figure 3. (a) The OEC as modeled in the 2011 XRD model of Umena et al.8 (b) Schematic depiction of atom labeling and first coordination sphere connectivity.

In the 2011 model, the pendant Mn ion (Mn4) is connected to the rest of the structure by an additional oxo bridge, while the pseudocuboidal unit is “opened” with nonbonding distances between the O5 bridge and the Mn ions (Figure 4). The Mn ions are ligated by aspartate (D1-Asp170 and D1-

Figure 4. (a) Metal−metal distances and bond lengths in the inorganic core of the 2011 XRD model.8 (b) Corresponding distances and bond lengths in the core of the XFEL-XRD 2015 model.69 Data from one of the PSII monomers is depicted in each case.

Asp342) and glutamate (D1-Glu333, D1-Glu189, and CP43Glu354) residues. D1-His337 provides the unique N-donor ligand to Mn1, and the C-terminus of the D1 protein (Ala344) bridges Mn3 and the Ca ion. Asp170 bridges the pendant Mn4 ion and Ca, with a strong tilt of the carboxylate toward CP43Arg357, suggesting a bifurcated ion/hydrogen-bond interaction. There are four terminal water-derived ligands, two coordinated to Mn4 (W1 and W2) and two to Ca (W3 and W4). Important residues in the second coordination sphere include His332, which hydrogen-bonds with the O3 bridge; 9480


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O5.56,81 A combination of these factors and the simple fact that the precise positions of O atoms are difficult to resolve in XRD when they are next to heavy Mn atoms70 might result in an apparent O5 position at longer distances from the Mn ions Mn3, Mn4, and secondarily Mn1 than would have been expected if O5 were a fully deprotonated oxo bridge. This suggestion was supported by EXAFS simulations,70 which also fit better with the idea that the 2015 XFEL-XRD model reflects the average of two or more states. 3.2. Heterogeneity in the S1 State. Although it is usual to think of the manganese cluster as having a unique structural identity, there is substantial evidence from methods that directly probe the electronic structure of the cluster to suggest that a single species is insufficient to explain observations on the S1 state and the S1−S2 intermediates. It is useful to draw a distinction between sample heterogeneity as the result of experimental procedures or handling limitations that may lead to artifacts in crystallographic models due to unintentional coexistence of different states (the Umena et al. model8 can be considered such a case) and physiological single-state heterogeneity that can arise naturally within one specific catalytic state and may even have functional significance. It must be recognized, however, that it might be impossible to distinguish between these two forms of heterogeneity in primary data or readily incorporate this consideration in data analysis. EXAFS studies have not provided any indication of heterogeneity in the S1 state,82 but it is questionable whether identification of minor structural differences are within the capabilities of the approach. It is worth mentioning a study by Kusunoki,83 who had suggested the presence of isomeric forms in the S1 state in an attempt to reconcile the Umena et al. XRD model8 with EXAFS.52 The Kusunoki models were related by tautomerization among titratable groups of the cluster and proton migration between terminal water ligands and secondsphere residues.83 With the benefit of hindsight, one can see that the attempt of this study was undermined by the assumption that the Umena et al. XRD model was an accurate representation of the S1 state of the OEC. A similar idea was explored by Petrie et al.,74 who suggested that tautomerism in the S1 state could explain certain structural differences between the crystallographic models of Umena et al.8 and Suga et al.69 However, the interpretation of the two XRD models as equally valid representations of the dark-stable state conflicts with their well-documented differences in X-ray damage and their distinct levels of agreement with the EXAFS of the S1 state. Moreover, the assumption of a low oxidation state assignment for the OEC (i.e., Mn(III,III,III,IV)) by Petrie et al. leads to high-spin ground states for these computational models, which to date have been impossible to reconcile with EPR data.56 Isobe and co-workers84,85 also explored the possibility of isomerism in the S1 state computationally and identified two forms of the cluster related by intramolecular proton transfer: in one of them, all of the oxo bridges were unprotonated and the terminal W1 and W2 ligands of Mn4 were present as H2O, while in the other, a proton was shifted from W2 to O5, creating a OH bridge. Similar forms of the S1 state and their corresponding magnetic and spectroscopic properties were studied by Krewald et al.,56 who concluded that protonation of the O5 bridge was unlikely. That study also showed that various models for the S1 state could lead to the correct spin singlet (S = 0) ground state and spin triplet (S = 1) first excited state, provided that the two Mn(III) ions are localized at the terminal sites (Mn1 and Mn4).56 More recently, Guidoni and

mixture of oxidation states, including species that do not form part of the normal catalytic cycle.61 Therefore, the Umena et al. model cannot be viewed as a representation of a single state (the S1 state) but must be considered as a spatially averaged representation of physiological and nonphysiological states.30,61,65 This is due to the X-ray-induced reduction of Mn ions to Mn(II), which had already been studied by X-ray spectroscopy and realized to have compromised earlier crystallographic work.66−68 This issue was addressed in 2015 with an XRD study by Suga et al.69 that utilized XFEL pulses to minimize radiation damage. The resulting model maintains the overall features of the previous one but drastically improves (Figure 4) the metal−oxygen bond lengths and brings the metal−metal distances into closer (but not perfect)70 agreement with EXAFS. The significant differences between the two XRD models confirmed that the reservations regarding the OEC structural parameters of the 2011 model were fully justified and that the 2015 model was improved precisely because of the better control of radiation damage and hence because of the avoidance of Mn reduction. However, this is in contrast to the view of Pace and co-workers, who regard both XRD models, as well as older ones, as equally valid representations of the darkstable state alone.71−75 This led to divergent conclusions regarding the composition of this state71−75 and the assignment of individual Mn oxidation states in line with the “low oxidation state scheme” that assumes an all-Mn(III) cluster in the S1 state.76,77 For further information on the debate between the “low” and “high” oxidation state paradigms, the reader is referred to relevant papers and reviews.56,78,79 Importantly, the quality of the Suga et al. XFEL-XRD model enabled a direct reading of Mn oxidation states.69 This is the case because the terminal Mn1 and Mn4 ions have clearly defined Jahn−Teller elongation axes, the structural signatures of high-spin d4 Mn(III) ions with occupation of the metal− ligand σ-antibonding dz2 orbital. This feature enabled Suga et al. to assign the two terminal Mn ions as Mn(III), yielding the oxidation state distribution III−IV−IV−III, and simultaneously to assign the orientation of Jahn−Teller axes as almost collinear along W1−Mn1−O5−Mn4−Asp342.69 The 2011 and 2015 XRD models offer a reliable basis for structure-based interpretation of other observations and for applications of quantum chemistry to the electronic structure and spectroscopy of the cluster. However, even the latest crystallographic model cannot be considered a final representation of the S1 state. Why is the picture incomplete? A simple bond-valence sum analysis of the 2015 model of Suga et al. would support formal oxidation state assignments of III− IV−III−II, which are incompatible with the known electronic structure of the dark-stable state. This implies that despite improving on the 2011 model, the Mn−O distances on average remain unsatisfactory. Another problem remains the position of the O5 bridge, which cannot be convincingly reproduced by otherwise highly reliable quantum-chemical methods. The discrepancy between the position of O5 in the crystallographic model and that in many different computational models was initially attributed56 to the possible presence of a nonnegligible amount of the S0 state in the PSII sample, either through radiation damage80 or because long dark adaptation without preflashing can lead to admixture of ca. 25% (or even more) of S0.70 According to computational models, the cluster in the S0 state most likely contains a protonated O5 bridge and a Mn3(III) ion with the Jahn−Teller axis pointing toward 9481


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before the S2 state is reached, leaving open the possibility of (unspecified) heterogeneity in the S1 state itself.97−102 These observations also have direct relevance for the emergence of structural and valence heterogeneity in the S2 state, which will be described in a subsequent section. Several ideas about the nature of this hypothetical heterogeneity have been proposed,83,92,93,102,103 but none of these ideas has been clearly supported by independent experimental evidence or quantum-chemical modeling. Synthetic tetramanganese complexes have been reported with the correct Mn(III)2Mn(IV)2 oxidation states and g values extremely similar to one but not both of the signals attributed to the S1 state (g ≈ 4.8 and g ≈ 12).104,105 Currently, no models of S1 state EPR signals have been advanced from quantum-chemical studies, leaving the observations and atomistic interpretations of EPR spectroscopy open to debate. A recent work that may point toward a possible way to attack this problem was reported by Paul et al.,106 who analyzed the electronic structure and spectroscopic features of a structural model of the OEC105 that contains a Mn3CaO4 cubane (III− IV−IV) with a fourth Mn(III) ion attached to one of the oxo bridges. The Jahn−Teller axes of the two Mn(III) ions align with the principal axes of the local fine structure tensors, and hence, their relative orientation determines the contributions of the two Mn(III) ions to the total D value of the complex. In Zhang’s complex, the perpendicular alignment leads to g = 12,105,106 whereas a model of the S1 state of the OEC with a quasi-parallel orientation of the Jahn−Teller axes leads to g = 4.9 due to a cancellation effect99,107,108 that results in smaller effective D (0.15 cm−1 vs 1.0 cm−1 for the perpendicular case).106 Although the Jahn−Teller effect of Mn(III) ions is recognized as a factor of structural deformation,87,109,110 this analysis106 suggests that it might also be the key for interpreting the conflicting EPR observations on the darkstable state of the OEC. In conclusion, advances in crystallography since 2010 have provided an unprecedentedly accurate view of the OEC in the dark-stable state, but this should not obscure the incomplete and averaged nature of crystallographic models. A way to advance our understanding is to clarify EPR observations on the S1 and S1YZ• states with atomistic models and high-level electronic structure analysis. This can reveal the right ways to approach the question of S1 heterogeneity and shed light on the transition to the S2 state.

co-workers reported that they could locate two almost isoenergetic minima with identical protonation states of all titratable groups that differ primarily in the Mn1−O5 and Mn4−O5 distances, with the O5 oxo located at a short bonding distance from either of the two terminal Mn ions.63 This study suggested that these two forms could be one way to rationalize the discrepancies between the XFEL-XRD model69 and the computational models of the OEC, although the presence of some percentage of S0 still had to be invoked for a fit to the XFEL-XRD model.63 The possible correspondence of these models with spectroscopic data was not examined. Although the connection between such computational studies and experimental data is still far from solid, they all suggest that structural heterogeneity is in principle possible in the darkstable state. A relevant crystallographic study was reported by Tanaka et al.,86 who suggested that under conditions of very low X-ray doses using conventional synchrotron sources, their XRD data for the S1 state could be fitted with two distinct structures of the OEC cluster, one for each PSII monomer, accommodated within an essentially identical coordination sphere. The two models differ mainly in the side of the cubane defined by Mn1−Mn2 and their oxo bridges, O1 and O3, with additional apparent differences in hydrogen-bonding interactions being tentatively assigned to different protonation states of secondsphere residues or water molecules.86 It is not clear how these specific models, the differences between them, and their differences from the Suga et al. XFEL-XRD model can best be rationalized, since a descriptive approach based on Jahn− Teller distortions may serve to categorize geometric data87,88 but offers no insight into their electronic structure origin and potential implications. Nevertheless, the above results call into question the assumption that the OEC centers in previous studies were uniformly in the dark-stable state and highlight again the dangers of viewing any given crystallographic model as a direct representation of a unique and well-defined structural entity. This point is important because the justified fascination with the increasingly available crystallographic models may lead us to overlook more complex information from other sources. This would be regrettable because observations from EPR spectroscopy of the S1 state, the S1YZ• intermediate, and the S1−S2 transition are still not fully explained with atomic models. EPR spectroscopy points toward heterogeneity in the S1 state, at least in a spectroscopic sense.89−91 EPR studies are complicated by the fact that the S1 state is an integer-spin species with a diamagnetic (S = 0) ground state,92 so only parallel-mode studies probing low-lying triplet (S = 1) states have been carried out. The first S1 signal to be reported was a featureless signal around g = 4.8,93,94 observed in spinach. A different signal, at g = 12 with resolved Mn hyperfine interactions, was reported later for cyanobacterial OEC.95 This second signal could also be induced in spinach by removal of two extrinsic PSII proteins, 96 suggesting that the spectroscopic response of the inorganic cluster in the S1 state is sensitive to minor structural perturbations. The two signals have not been observed simultaneously, and even their common origin has been questioned.95 Additional information comes from studies of metalloradical states created upon oxidation of the redox-active tyrosine residue (YZ) that mediates electron transfer between the OEC and the charge separation site of PSII. Such “split” S1YZ• signals showed that spectroscopic heterogeneity is present

4. THE S0 STATE Going backward in the catalytic cycle, the S0 state differs from the dark-stable S1 state by a single electron and proton. X-ray spectroscopy had indicated that the S0 to S1 transition involves Mn-centered oxidation on the basis of the flash-numberdependent shift in the Mn K-edge.18−20 EPR studies showed that the S0 state is paramagnetic with an antiferromagnetically coupled ground state of spin S = 1/2,111−116 and 55Mn ENDOR studies demonstrated the absence of a Mn(II) ion in the S0 state,60,117 thus fixing the Mn states to Mn(III)3Mn(IV). It is noted that this assignment contradicts the alternative “low oxidation state scheme”, which requires the oxidation states Mn(II)Mn(III)3 in the S0 state.118 Intermetallic distances from EXAFS had suggested elongated distances in S0 compared with S1, in line with the more reduced metal ions.32 Although direct three-dimensional structural information is lacking for the S0 state, structural models have been obtained computationally by extrapolating backward from S1 models 9482


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ACS Catalysis with the addition of one electron and one proton. With reference to the S1 state, in which the terminal Mn1 and Mn4 ions are found as Mn(III), various theoretical studies have converged to the conclusion that the additional electron in the S0 state is most probably localized on the Mn3 ion,56,119−121 leading to the oxidation state arrangement III−IV−III−III. In line with EPR/ENDOR studies, solutions that involve Mn(II) ions are strongly disfavored.56,120 Such models agree with EXAFS,119 but it remains unclear how the Jahn−Teller axes of the three Mn(III) ions are oriented or indeed whether a unique stable orientation exists.56 This relates to the uncertainty in protonation level and pattern. Following a probable assignment for the S1 state (i.e., W1 = H2O and W2 = OH), an additional proton in the S0 state is most likely accommodated at W2 or either the O4 or O5 bridge. If W1 = W2 = H2O in the S1 state,61 then the additional proton can be accommodated only by one of the bridges; Pal et al.119 favor the O5 bridge as the protonation site in this case. It is also conceivable that a redistribution of protons occurs in the S0 state compared with the S1 state, so that, for example, both the O4 and O5 bridges are protonated. Clarifying the protonation pattern in the S0 state is important because it relates to substrate identification, given that reconstitution of the S0 state after dioxygen evolution involves the binding of a water molecule and possibly its deprotonation by concomitant incorporation as a bridge. The correct assignment of a protonated bridge further relates to the identification of proton egress pathways, a point that will be discussed later in the context of the likely roles of water channels. Several alternatives were investigated by Krewald et al.,56 who concluded that calculations do not clearly support a unique model but nevertheless favor a structure with a protonated O5 bridge. Multifrequency/multiresonance EPR studies by Lohmiller et al.81 confirmed the oxidation state assignment of individual Mn ions with the unique Mn(IV) ion positioned at Mn2 and suggested that observations are most consistent with the presence of one exchangeable oxygen bridge, also assigned to protonated O5.81 The above interpretations are consistent with density functional theory (DFT) models of the S0 state that are computed to have a spin doublet ground state (Figure 5).56,81 The computational study of Pal et al.119 supported a higher overall protonation state (W1 = W2 = H2O and O5 = OH) as a good fit to EXAFS, but this type of model was found to yield a high-spin ground state and hence was not judged to be consistent with EPR by Krewald et al.56 It should be recognized, however, that the presence of multiple closely interacting Mn(III) ions represents a nonideal electronic situation for DFT methods. For example, the computed 55Mn hyperfine coupling constants for S0 models do not show as good agreement with experiment as those reported for higher Si states13,110 because even though the ground states of the two most favorable S0 models (S0-A and S0-B in Figure 5) are consistent with experiment, their isotropic 55Mn hyperfine coupling constants117 produce a more compressed range of values than experimentally observed.56 It is also possible that computational models that assume the validity of crystallographic backbone constraints may be missing second-sphere differences between the S1 and S0 states.122 Computed relative energies may also be less reliable than in other states because of the energetic proximity of local Jahn−Teller minima in contrast to higher Si states,56 but on the other hand, this is not necessarily unphysical because the energetic accessibility of several states could explain the high

Figure 5. Selected plausible protonation patterns, oxidation state distributions, and Jahn−Teller axis orientations of EPR-compatible computational models for the core of the S0 state of the OEC (all of the amino acid residues and Ca-bound waters have been omitted for clarity).56,81 All of the models have a low-spin (S = 1/2) ground state.

species dependence of S0 state signals and their sensitive response to external perturbations.115,116 Viewed from the perspective of the likely deprotonation mechanisms, Siegbahn favored a model for the S0 state similar to S0-A in Figure 5 and suggested that in the S0−S1 transition the proton of the O5 bridge is initially abstracted by a proximal water molecule located at hydrogen-bonding distance from O5H.121 However, a potential problem with this idea is that no such water molecule is visible in any of the recent crystallographic models of PSII.8,69 Saito et al.123 favored instead a model for the S0 state in which the O4 bridge is protonated (similar to S0-C in Figure 5), acting as a hydrogenbond donor to a crystallographically resolved water at the end point of a chain of waters that terminates at the O4 site. Under this assumption, they showed that upon oxidation of the model to the S1 state, the O4H proton is easily lost to this chain of waters.123 This idea will be further discussed below in relation to the channels and the accessibility of small molecules. At this point it is fair to state that there are no sufficient experimental constraints for a reliable evaluation of these models. Although many possibilities have been excluded and the Mn oxidation states are known, finer details of the electronic structure and protonation pattern of the S0 state as well as of the deprotonation mechanism that accompanies the S 0 −S 1 transition remain uncertain. Further input from experimental studies is required to elucidate these points. A more refined approach to the characterization of the S0 state could combine advanced magnetic resonance methods with labeling techniques and more fully utilize information from intermediates of the S0−S1 transition. 9483


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5. THE S2 STATE: STRUCTURE−SPECTROSCOPY CORRELATIONS With the exception of distances from EXAFS, which suggest minimal structural changes compared to the preceding S1 state consistent with a single electron loss (Figure 2), no other direct structural information on the S2 state of the OEC exists. By contrast, there is a tremendous amount of information derived from EPR spectroscopy and associated magnetic resonance techniques. The S2 state exhibits two signals depending on the experimental conditions. A characteristic multiline signal at g ≈ 2 was the first to be reported and proved that the Mn ions were exchange-coupled into an antiferromagnetic total spin state of S = 1/2.124 A second type of EPR signal was identified for the same state, belonging to a higherspin form. In plants, this is associated with a g ≈ 4.1 signal125−130 arising from a species with an intermediate spin of S = 5/2 in its ground state, while similar signals at higher g values are associated with cyanobacterial PSII.131,132 Importantly, the two signals are interconvertible,128,133−135 confirming that they represent ground-state isomeric forms of the manganese cluster. Among the seminal contributions of spectroscopy have been the 55Mn ENDOR experiments by Britt and co-workers,38,136 which suggested that three of the ions were more strongly coupled than the fourth, implying a “Y-shaped” or “3 + 1” arrangement (the “dangler” model). The correct derivation of the arrangement of Mn ions from the magnetic properties of the cluster, in disagreement with prevailing structural models such as the “dimer-of-dimers” idea, has to be recognized as a historical achievement of EPR spectroscopy. Further progress in structural refinement has rested on the advent of atomic-resolution crystallographic models8 and the use of quantum-chemical approaches for making connections w ith s pectroscopic observables.48,49,137−139 A pivotal point in the structural understanding of the OEC has been the elucidation of the origin of the two EPR signals in the S2 state in terms of precise atomistic models. Starting from the 2011 XRD structure of PSII, optimizations with large quantum cluster models were carried out using total charge and spin multiplicity assignments consistent with those expected for the Mn(IV)3Mn(III) ions of the S2 state.110 Large stabilization was observed upon energy minimization, with significant movement of bridging oxygen atoms compared with the crystallographic model and contraction of the Mn− Mn distances in line with EXAFS. The optimizations led to two minima that could be described as valence isomers, since they differed only in the location of the unique Mn(III) ion and the associated binding mode of the central oxygen bridge, O5 (Figure 6a).110 In one of the isomers, termed “open cubane” (SA2 ), Mn1 is the Mn(III) site and O5 binds tightly to Mn4; in the other, termed “closed cubane” (SB2 ), the Mn1− Mn3 ions form a proper Mn(IV)3CaO4 cubane with O5 closely bound to Mn1, while Mn4 is the Mn(III) site. In both isomers, the Mn(III) ion is five-coordinate and characterized by axial elongation with the Jahn−Teller axis pointing toward O5, creating in each case an apparent empty coordination site in the interior of the Mn4CaO5 cluster. DFT calculations indicated that the valence isomers are very close in energy, the open cubane S2A being favored by ca. 1 kcal mol−1.110 Additionally, they were interconvertible over a low barrier, and the transition state found corresponded to a contraction of the cluster that facilitated electron transfer between the

Figure 6. Valence isomers in S2 of the OEC: (top) geometries of the Mn4CaO5 cores (ligating residues have been omitted for clarity); (middle) main exchange coupling constants (in cm−1) with the resulting ground spin states; (bottom) simulated X-band EPR spectra.

terminal Mn ions with a concomitant exchange in the bonding of the O5 bridge.110 These values for the relative energetics agree well with subsequent QM/MM molecular dynamics investigations,140 with higher-level theoretical studies that utilized the domainbased local pair natural orbital implementation of coupled cluster theory,141 and with recent experimental measurements of the energy difference.142 It has been reported that the two components can also be differentiated by X-ray spectroscopy.143 Isobe et al.85 independently identified similar structural patterns (termed “right-elongated” and “left-elongated”, corresponding to what were called open and closed cubane, respectively, in the prior study110). These models were not related to EPR observations, but the energy difference between the isomers was broadly consistent with that in the prior study if no additional water association was assumed, in which case the closed cubane (left-elongated) form was reported to be strongly stabilized.85 Although the majority of computational studies are in mutual agreement and reproduce the experimental observations regarding the relative stabilities of the two conformations, a few computational studies have reported imbalanced energetics, overstabilizing either the open cubane or closed cubane conformer.144−146 Such errors may originate from methodological issues63,106,147 related to the model size, the imbalanced treatment of the environment in terms of inclusion or exclusion of second-shell charged entities, the treatment of dispersion effects, configurational sampling, or perhaps the incorrect assignment of protonation states of ligands and second-sphere residues. The magnetic properties are the most important aspect of these isomers because they establish their one-to-one correspondence with the observed EPR signals of the S2 state. Broken-symmetry DFT calculations showed that the two isomers differ in the sign and magnitude of the pairwise 9484


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ACS Catalysis exchange coupling constants (Figure 6b).110 In the open cubane isomer (SA2 ), the three dominant exchange coupling pathways alternate among antiferromagnetic (Mn1−Mn2), ferromagnetic (Mn2−Mn3), and antiferromagnetic (Mn3− Mn4), leading to a low-spin S = 1/2 ground state. By contrast, in the closed cubane isomer (SB2 ), the Mn1−Mn2 pathway becomes ferromagnetic, and a higher total spin for the ground state is obtained (S = 5/2). For SB2 the magnetic level separation is small, so a minor perturbation of the important Mn3−Mn4 superexchange pathway, for example by perturbation of the hydrogen-bonding network involving O4,148,149 can result in a ground spin state higher than S = 5/2. Hence, such secondsphere modifications might explain the origin of g > 4 signals.150 Therefore, the two isomers correspond to the spin states assigned to the two EPR signals of the S2 state, as was additionally demonstrated by explicit simulations of EPR spectra (Figure 6c).110 It was later shown55 for synthetic models53,54 that the closed cubane Mn(IV)3CaO4 subunit is an intrinsically high-spin S = 9 /2 unit because of diminished superexchange interactions due to the acute M−O−M angles. Thus, the total spin state of S = 5 /2 for S2B can be considered as arising from effective antiferromagnetic coupling of this high-spin subunit with the outer Mn4(III) ion (local spin S = 2). This also means that the older Ferreira et al. model of the OEC,36 along with any computational models derived from it,41,44 could not have been consistent with the S2-state EPR spectra of the OEC. Insufficient consideration of spectroscopic data in structural studies and avoidance of dealing with the complexities of magnetic coupling in most computational work had masked this fundamental problem for years. A final confirmation of the assignment of these structural forms to the spectroscopically observed states was provided by the 55Mn isotropic hyperfine coupling constants (HFCs) (absolute values in descending order: 280, 212, 201, and 176 MHz), which reproduced quite accurately the range and distribution (one large, two medium, and one small) reported in various ENDOR studies of the S2 state.38,117,151 The 55Mn HFCs were also used as a criterion to elucidate the protonation states of the Mn ligands, supporting the assignment W1 = H2O and W2 = OH as most consistent with the ENDOR data.50,56,152 The precise definition of the structural heterogeneity in the S2 state provides a platform for structural interpretations of experiments documenting the response of the two EPR signals to a range of treatments.89,134,148,153−157 More significantly, however, it is likely that the valence isomerism in the S2 state is part of a gating mechanism that regulates access to higher Si states of the cycle. In this respect, investigations of the access of small molecules (considered as “substrate analogues”) to the OEC site are crucial for studying the S2 state and the S2−S3 transition, identifying substrate binding sites, and understanding the role of the protein matrix in catalytic control. Most such studies focus on methanol and ammonia because these perturb the properties of the cluster without necessarily abolishing the activity. Before we discuss the interaction between the cluster and these molecules, it is necessary to discuss the water channels of PSII that are associated with the cluster and control access to the active site by connecting the OEC to the exterior of the enzyme.

6. PSII CHANNELS RELEVANT TO THE OEC 6.1. Architecture and Possible Roles of Water Channels. In contrast to electron transfer pathways within PSII, which are reasonably well understood in terms of components and directionality, key questions remain open regarding the atomic definition of pathways involved in the flow of water as the substrate and dioxygen as the product as well as the transfer or translocation of protons. To address these questions, it is necessary to identify and structurally characterize water channels that connect the OEC with the exterior of PSII and subsequently to establish the possible roles of these channels and related hydrogen-bonding networks in enabling or inhibiting the flow of specific molecules and protons to and from the water oxidation site.158−161 It had long been recognized that the OEC site, buried within the membrane-embedded part of PSII, would require appropriate channels and pathways to enable water access and proton removal. Moreover, in view of the complex multielectron chemistry of water oxidation, these channels have to moderate access in a way that substrate delivery and proton egress are directional and ordered while harmful or wasteful reactions are avoided. The first reliable crystallographic models of PSII provided the basis for the first analyses of channels for the transfer of water on the donor side and plastoquinone on the acceptor side as well as of the products of water oxidation and plastoquinone reduction.162 Noble gas derivatization of PSII crystals demonstrated the accessibility of several channels to other molecules, supporting their involvement in dioxygen release.163 Computational studies have further refined our view of channels and their possible roles.164 For example, molecular dynamics simulations149,165−168 have contributed toward circumventing the limitations of simple cavity analysis of crystal structures, allowing a more physically realistic study of water channels and water diffusion165,166 and even characterization of water permeation energetics.167 Methanol accessibility has also been of particular interest169 because methanol displays a specific interaction with the OEC (discussed in a later section of this review) that has been the subject of many spectroscopic investigations. These studies characterized several water channels and reached similar but not identical conclusions about how the OEC is connected to the lumen. Reasons for discrepancies include the use of rigid crystal structures versus molecular dynamics and of different methodologies and algorithms to analyze the experimental or computational structures. Furthermore, uncertainties arise because water diffusion pathways implicating the OEC branch and can be subject to transient changes,165 thus establishing diverse nonpermanent connections with different possible entrance/exit points. Nevertheless, three water channel end points can be clearly identified in the immediate vicinity of the OEC. Two end points are associated with different sides of the Mn4 site (channels A and B), while the third one (channel C), which may branch at a short distance from the cluster, is associated with the Ca ion (Figure 7). The end point of the first water channel (A in Figure 7) involves a water molecule (labeled W5) that hydrogen-bonds to the O4 bridge of the cluster. This channel connects the OEC with the lumen at the interface of the cyanobacterial PsbU and PsbO proteins and can be identified with the “narrow” channel described by Ho and Styring,169 “E/F” in Gabdulkhakov et al.,163 “channel 2” in Vassiliev et al.,166 “4c” in 9485


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Another channel system (indicated as B in Figure 7) starts in the vicinity of Mn4 and leads to PsbO, likely involving the proximal chloride ion and residues D1-Glu65, D1-Arg334, and D2-Glu312.159,175−178 This channel has been associated with proton release on the basis of the calculation of a monotonic increase in pKa values of titratable residues175 as well as FTIR and mutation studies.176−178 Molecular dynamics studies by Bondar and co-workers on the site of the interaction between the PsbO subunit and PSII, the role of PsbO carboxylates, and the dynamics of the relevant hydrogen-bonding network are fully consistent with a role of this channel (and of PsbO) in proton transfer.179−181 Moreover, the W1/H2O molecule is the most likely deprotonation site in the S2−S3 transition,174,182,183 with D1-Asp61 acting as the proton acceptor,36,51,175,184−186 to enable oxidation of Mn4 by the tyrosine radical and advancement to the S3 state.28,174,182,187,188 This deprotonation would be compatible with channel B serving in proton egress as well as with the proposed participation of the proximal chloride in proton transfer.184,189 Finally, the Ca-bound waters and those in the vicinity of the O1 bridge may be regarded as part of another channel system (C in Figure 7, known also as the “large” channel system169) that leads to PsbV through at least two distinct pathways. All conceivable functions have been proposed for the channel systems originating at this site. In a view complementary to the most likely assignments mentioned above for the other two channels, the hydrophobic nature of channels on this side of the OEC and the high barriers for water permeation have led to the suggestion that they are better optimized for dioxygen release,167,169 which would be consistent with the idea that the calcium ion may facilitate the release of newly formed dioxygen.190 On the other hand, if a Ca-bound water eventually serves as a substrate in O−O bond formation,44,191−197 then this channel might also be viewed as a substrate delivery pathway. Although it would be premature to dismiss this possibility, it has limited supporting experimental or computational evidence. Lastly, this channel system has been implicated in proton translocation or transfer.8,28,198−200 It is accepted that oxidation of Tyr161 (YZ) by P680+• is accompanied by a shift of the phenolic proton to the imidazole of His190, which forms a short, barrierless hydrogen bond with the tyrosine201 and with Asn298 as part of a hydrogen-bonded triad. The initial proton shift from Tyr161 to His190 might be followed by further proton translocations and possibly release of a proton to the lumen.28,198 Relevant for proton transfer is the tight hydrogen-bonding network in this area165,168,202 as well as the observation that Asn298 is functionally indispensable203,204 and may participate as a secondary base in the formation of the S2YZ• intermediate.198 In conclusion, although likely roles for the three channels discussed here are water delivery for A, proton egress for B, and dioxygen release for C, the available data do not justify a high degree of confidence. Additionally, it cannot be excluded that any of these channels is bifunctional. This would be important particularly if proton release does not proceed from a single pathway.123,175,183,188 Relevant to this is the suggestion that water clusters in the immediate vicinity of the OEC may act as transient proton acceptors at multiple points of the catalytic cycle.205−208 This concept has not been explored to date in atomistic modeling studies. It is also important to note that the “end-point” water molecules of these three channel systems and all of the water ligands of Mn4 and Ca are part of a common extended hydrogen-bonding network. It is not clear

Figure 7. Water channel end points associated with the OEC.

Umena et al.,8 and “Path3” in Ogata et al.168 The W1 ligand of Mn4 could be considered as associated with this channel. Echoing a suggestion made in an earlier static solvent contact surface analysis169 of the 3.0 Å resolution crystallographic model of PSII,39 Saito et al.123 have proposed that this channel may be involved in deprotonation during the S0−S1 transition, with the ordered waters accepting the proton of the O4 bridge. This model assumes that O4 is protonated in the S0 state and is a hydrogen-bond donor to the end-point water of the channel (i.e., an inverse situation compared with that depicted in Figure 7). However, as discussed above, experimental81 and computational studies56,119 instead favor O5 as the most likely candidate for a protonated bridge in the S0 state. Therefore, it is possible that the observation of O4H deprotonation in the simulation of Saito et al.123 was dictated by the starting computational model, i.e., the energetically unfavorable assumption of O4 protonation. Although a possible role in proton transfer requires further investigation, this channel has been predominantly associated with the delivery of water and small molecules such as ammonia and methanol. Specifically, NH3 was shown to substitute for W1/H2O as the ligand of Mn4 in the S2 state,156,157,170−172 while methanol was suggested to interact with the OEC by second-sphere binding at or close to the position of the end-point water (W5) of channel A,148,173 disturbing the hydrogen-bonding network that involves O4. Both cases are consistent with involvement of channel A in the delivery of these molecules to the OEC. In terms of water accessibility, a landmark study by Vassiliev et al.166 showed that water permeation to the OEC faced the lowest barrier through this channel according to multiple steered molecular dynamics simulations. Subsequently, a quantum-chemical treatment of water binding through this channel was presented by Retegan et al.,174 who computed a low-barrier transition state for attachment of the end-point water of the channel to Mn4 in the context of the “pivot” mechanism for water binding at the final stage of the S2−S3 transition.174 9486


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diameter of the channel compared with higher-plant D1-Ala87. The substitution affects the interaction of Arg357 with the O4 bridge and hence the exchange coupling between the Mn3 and Mn4 ions. This is a critical parameter that in turn regulates the total spin state of the cluster in a given conformation. More importantly, this difference in local channel architecture likely affects the interactions of small molecules with the OEC. The above study suggested that the D1-N87A substitution may directly explain the different interaction modes of methanol with the OEC in cyanobacteria and higher plants.149 This is consistent with the interaction site of methanol as assigned by quantum-chemical studies148 in relation to EPR data173 and provides strong support for the assignment of channel A as a water transport channel. Banerjee et al.214 performed a study of D1-N87A and D1N87D variants of cyanobacterial PSII from Synechocystis and reported that the EPR and flash-induced FTIR spectra of the S2 state for both variants were similar to those of wild-type Synechocystis PSII core complexes. The D1-N87D variant showed decreased cycling efficiency in flash-induced dioxygen evolution, but the efficiency of D1-N87A PSII was similar to that of wild-type PSII. Interestingly, the D1-N87A substitution was shown to perturb the chloride-binding site, mimicking the chloride-binding characteristics of spinach PSII.214 This study points to a high level of interconnectedness and interaction of structural factors in the environment of the OEC. It would be highly desirable to employ similar studies in the explicit investigation of channel architecture and small-molecule accessibility.

whether water exchange among these three channels over the “surface” of the Mn4CaO5 cluster by concerted motions of W1/W2 or W3/W4 is facile. Studying the effect of directed mutations at critical channel residues on specific S-state transitions209 could make an important contribution toward a better understanding of the roles of the channels, particularly in relation to proton egress. 6.2. Differences among Species. Important information on the architecture and roles of water channels can be derived from comparative studies among species. Sakashita et al.210 presented a comparison of cyanobacterial and plant PSII (using the cryo-electron microscopy structure of spinach PSII211), comparing and contrasting the channel architectures as well as identifying likely salt bridges. Their conclusion was that the cyanobacterial channels associated with the O4 and O1 bridges of the OEC, O4-PsbU and O1-PsbU/V, are structurally conserved as the channel that proceeds along PsbP toward the protein bulk surface in plant PSII (O4-PsbP and O1-PsbP),210 and they related these observations to the stabilizing role of the PsbP unit in higher plants.212,213 In their concise analysis of second-shell residues and hydrogenbonding networks around the OEC, Vogt et al.160 identified D1-87 as the site of the most significant variation between cyanobacteria (Asn) and higher plants (Ala). A subsequent computational study focused on characterizing such differences between the structure of channels close to the OEC in cyanobacterial and higher-plant PSII using molecular dynamics simulations.149 Higher-plant PSII has not yet been crystallographically characterized but is known to have very high homology with cyanobacterial PSII in the core proteins D1, D2, CP43, and CP47. Using the amino acid sequences of spinach (Spinacia oleracea), Retegan and Pantazis149 created a chimeric computational PSII model by mutating the four core proteins of cyanobacterial PSII into those of spinach. Longtime-scale (up to 500 ns) all-atom molecular dynamics simulations were subsequently used to compare the cyanobacterial and chimeric “spinach-like” PSII models. With respect to the three water channel end points discussed here, the most significant result of that study was the characterization of the structural effect of the proximal substitution D1Asn87 (T. vulcanus) to D1-Ala87 (S. oleracea). This is the only channel-related substitution found close to the OEC and affects the structure of channel A close to its point of termination at the O4 bridge of the OEC (Figure 8). The D1-Asn87 residue hydrogen-bonds to CP43-Arg357 and the backbone carbonyl of CP43-Glu354, restricting the

7. INTERACTION OF SUBSTRATE ANALOGUES WITH THE S2 STATE 7.1. Methanol Interaction. Methanol is an important spectroscopic probe of the OEC because it interacts with the cluster in a noninhibitory way, modifying its electronic structure and EPR spectra.94,100,114,116,154,157,173,215−227 The most important effect of methanol is the increased energy gap between the ground and first excited states of the OEC, specifically stabilizing the low-spin ground states of the S0 (S = 1 /2), S1 (S = 0), and S2 (S = 1/2) intermediates. In addition, it selectively favors the g ≈ 2 multiline signal in the S2 state (attributed to the “open cubane” form). Cyanobacteria are less sensitive to methanol compared with higher plants,115,154,228 suggesting that the interaction mode might not be identical between species. Electron spin−echo envelope modulation (ESEEM) experiments with deuterated methanol in the S2 and S0 states217,220,229 have provided contradictory interpretations, with the inferred Mn−2H distances suggested to be consistent either with direct ligation of methanol to Mn4 by displacement of a terminal water ligand or to Mn1 by displacement of Glu189154,223 or with no direct binding at all.229 Oyala et al.173 more recently reported pulsed EPR studies with 13C-labeled methanol in the S2 state of spinach PSII. The 13 C hyperfine interactions provided evidence against the direct binding of methanol to manganese, while maps of the 13C dipolar hyperfine couplings identified two regions around the cluster as most likely for methanol interaction, either close to the Ca ion or in the vicinity of Mn4. The magnetic and spectroscopic data were used to evaluate a large number of computational models in a screening study by Retegan and Pantazis.148 After systematic sampling of methanol positions and poses around the manganese cofactor, most of the models

Figure 8. Differences between the end points of O4-terminating channel A in (left) cyanobacterial and (right) spinach-like models of PSII. 9487


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possibly hydrogen-bonding to the backbone of Ala188 and Gly171.230 Yata and Noguchi231 reported that FTIR difference spectra for the S1−S2 transition showed methanol-induced changes in amide bands with little change in the bands of carboxylate groups, histidine side chains, and a water network in the vicinity of the manganese cluster. This is consistent with the absence of a direct interaction of methanol with the inorganic cluster and suggests that methanol replaces a proximal water molecule in a water channel and interacts with a main-chain amide.231 Although the assignment of the delivery channel is rather well supported,148 these two new studies provide motivation to revisit and refine the previous computational models, which did not extend sufficiently far from the Mn cluster and did not sufficiently explore the possibility of a secondary interaction site. Future spectroscopic studies are also necessary in order to eventually reconcile existing observations with each other and with theoretical models. Comparative studies of the S2 state in spinach and cyanobacteria, and possibly also in mutants, would be particularly useful for probing differences in the methanol interaction mode among organisms and for supporting identification of specific access pathways. 7.2. Ammonia Interaction. In contrast to methanol, ammonia is known to interact more closely with the manganese cofactor and exhibits a more complex phenomenology with two types of interaction involving at least two sites: a noninhibitory interaction with direct ligation to the Mn cluster and a second-sphere inhibitory interaction at a site competitive with chloride.232−238 The effect of the interaction with NH3 (or NH4+) on the spectroscopy of the manganese cluster and the efficiency of water oxidation have been studied extensively.156,171,172,219,236−245 The chloride-independent binding of NH3 gives rise to an altered multiline (S = 1/2) signal in the S2 state,236 indicating that it perturbs the low-spin or open cubane form of the OEC and slows steady-state oxygen evolution.234,239 Pulsed EPR ESEEM experiments reported in 1989 had shown large isotropic 14N and 15N hyperfine couplings, proving direct ligation to a Mn ion.238 Additionally, the high asymmetry of the quadrupole interaction for the 14N nucleus suggested an asymmetric environment that would be hard to realize for a terminal NH3 ligand; instead, it seemed more reasonable that ammonia is deprotonated and incorporated into the OEC as an amido (NH2) bridge. This idea was accepted until recently and was supported by Brudvig and co-workers, who proposed that ammonia binds as a bridging ligand (in protonation states that can range from amido to fully deprotonated nitrido) in place of the O5 bridge.103,243 This was suggested to be consistent with early EXAFS observations240 as well as with the reported decrease in the OEC reduction potential upon binding of ammonia.243 However, it is hard to see how such a disruption of the Mn4O5Ca cluster would be noninhibitory. An alternative suggestion emerged from more recent combined spectroscopic and computational studies.156,157 Using a combination of pulsed magnetic resonance techniques (ELDOR-detected NMR) and time-resolved membrane inlet mass spectrometry, this work demonstrated that the 17O hyperfine couplings for solvent-exchangeable oxygen sites and the substrate exchange kinetics are not significantly perturbed by the binding of ammonia.156,157 The quantum-chemical model developed to explain these observations suggested that ammonia binds to the Mn4 site as a terminal ligand, replacing W1 (Figure 10).156,157 The model explains the unexpectedly

were eliminated because they could not reproduce the observed effect on the spin states, and all of the models involving direct ligation of methanol to a Mn ion were confirmed to be incompatible with the data of Oyala et al.173 because the methanol 13C dipolar hyperfine coupling parameters |T| would be an order of magnitude larger than the experimental ones. Of the two models that correctly reproduced the stabilization of the S = 1/2 ground state, one involved direct interaction of methanol with the calcium ion (replacing W3) and the other involved binding of methanol at the end point of channel A (see Figure 7), replacing the water molecule (W5) that normally hydrogen-bonds to the O4 bridge. Consideration of the 13C isotropic and dipolar hyperfine coupling parameters clearly favored the latter model (Figure 9), for which the computed |Aiso| and |T| were

Figure 9. Comparison of the O4 hydrogen-bonding environment in (left) the native OEC and (right) the quantum-chemical model that best reproduces the magnetic and spectroscopic data on methanol interaction. Adapted from ref 148, published by The Royal Society of Chemistry.

0.02 and 0.24 MHz, compared to the experimental values of 0.05 ± 0.02 and 0.27 ± 0.05 MHz, respectively. Importantly, in the model that best fits the data, methanol is positioned so that O4 remains without a hydrogen-bonding partner. This is key for explaining the “methanol effect”: the absence of hydrogen bonding to O4 results in enhancement of the superexchange interaction between Mn3 and Mn4. The stronger J 34 antiferromagnetic coupling in turn leads to stabilization of the low-spin states of the OEC (e.g., S = 0 in the S1 state, S = 1 /2 in the S2 state), increasing the energy gap between the ground and first excited states.148 In view of the difference between species149 identified at the region of the channel where methanol is suggested to bind148 (compare with Figure 8), it can be conjectured that this model might be most appropriate for higher-plant PSII, whereas the more constricted channel in cyanobacteria resulting from the hydrogen bond between CP43-Arg357 and D1-Asn87 could inhibit a similarly close approach of methanol. A recent proton-matrix ENDOR study by Nagashima and Mino230 on the S2 state employing CH3OH and CD3OH concluded that the deduced Mn−H distances were shorter than the Mn−C distances, which implies that MeOH is oriented with the methyl group closer to the Mn ions. Two likely positions of methanol molecules were suggested, one close to Mn1 and one close to Mn4, with the OH groups 9488


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is possible at a Mn(III) site, that the high-spin closed cubane form of the S2 state after ammonia addition to Mn4(III) would undergo a valence rearrangement to resemble instead the oxidation state distribution of the open cubane form with Mn1(III), and that even though it retains the bonding topology of the high-spin form, the associated changes in electronic structure might cause the final species to actually switch its spin state to S = 1/2 and develop a spectroscopic signature that resembles an ammonia-modified multiline signal, i.e., a modified low-spin form. At this point, however, no direct computational support exists with respect to the spin state and EPR properties of the NH3 addition model of Askerka et al.246 The NH3 addition model was evaluated in terms of energetics by Guo et al.,248 who reported that the barriers for the proposed process were considerably higher than for the W1 substitution and that the conjectured rearrangement of Mn oxidation states was not observed.248 A detailed study of inhibitory and noninhibitory NH4+/NH3 binding based on time-resolved O2 detection, recombination fluorescence, and FTIR difference spectroscopy offered significant new information on this highly complex system but could not clearly distinguish between the specific models discussed above.245 A potentially more decisive experimental evaluation was presented by the ESEEM and ENDOR study by Marchiori et al.172 These authors reported very small changes in the 55Mn hyperfine tensors associated with the Mn1 and Mn4 ions, suggesting that there is very little change in the geometric or electronic structure of the cluster upon ammonia binding. Furthermore, the absence of any change in the width of the 1H ENDOR spectra excluded protonation of the O5 bridge upon ammonia binding. These observations appear to be at odds with the central assumptions of the NH3 addition “carousel” model and more consistent with the NH3/W1 substitution model of Figure 10.172 Nevertheless, explicit calculations of the magnetic properties of both models would be required in order to make comparisons with the new data of Marchiori et al.,172 while additional experiments using, for example, HYSCORE would be highly desirable. Small-molecule accessibility to the OEC and the multitude of connected effects will certainly remain subjects of intense studies in the near future. A complete understanding of the inhibitory versus noninhibitory interaction of NH3/NH4+ in particular remains elusive.244,245,249 Here we would simply highlight the general conclusion that regardless of their specific details, all of the recent models for the interaction of ammonia and methanol with the OEC, in connection with the differences in channel architecture among species, suggest that the water channel that terminates at O4 is the most likely candidate for access of substrate analogues. This in turn makes it the most likely candidate for water delivery to the OEC, which is of direct relevance for the S2−S3 transition.

Figure 10. A spectroscopically consistent model of ammonia binding in the S2 state by substitution of the terminal W1 ligand of Mn4.156,157 Adapted from ref 157, published by the PCCP Owner Societies.

high quadrupole asymmetry,157,171 which results from the involvement of the NH3 hydrogen atoms in three hydrogen bonds of distinct nature: a strong interaction with the carboxylate of D1-Asp61 and two weaker interactions with the backbone carbonyl of D1-Ser169 and a solvent water. Since this type of ammonia interaction with the OEC does not inhibit dioxygen evolution, this model is suggested to exclude W1 as a substrate. This interpretation was supported in terms of energetics and spectroscopic properties by an exhaustive study of many alternative chemical models by Schraut and Kaupp.170 Further support for the suggestion of NH3/W1 substitution came from an ESEEM study by Oyala et al.171 using a D1-D61A mutant. This work showed that the ammonia 14 N hyperfine couplings and nuclear quadrupole parameters were the same in the wild-type and mutant PSII but that the nuclear quadrupole asymmetry was greatly diminished in the alanine mutant, confirming that ammonia forms a hydrogen bond with Asp61.171 More recently, a variation of this model was proposed246,247 in which NH3 does not substitute for W1 at the Mn4(IV) ion of the low-spin (S = 1/2) open cubane form (SA2 ) but is added as a sixth ligand to the Mn4(III) ion of the high-spin (S = 5/2) closed cubane form (SB2 ). In this case, the W1 and W2 ligands are suggested to move in a “carousel” fashion toward the Mn1−Mn3-bridging O5 (Figure 11). Ammonia thus occupies the former W1 site and can hydrogen-bond to Asp61. The model also requires O5 to be protonated. Protonation of O5 was suggested to occur by proton transfer from W2, which is required to be present as H2O in the S2 state. The series of central assumptions in this scenario are that ammonia binding

8. THE S2−S3 TRANSITION The transition from the S2 state to the S3 state is one of the most complex and contentious steps in the catalytic cycle of the OEC, particularly when it comes to translating the various observations into atomic models. Fundamental questions in this transition concern the sequence of deprotonation, Mn oxidation, and water binding as well as the role of S2 state heterogeneity. It would be hard to condense here the vast literature and experimental data on the S2−S3 transition and its possible intermediates. Instead we will attempt to highlight

Figure 11. Schematic representation of the NH3 addition (“carousel”) idea of Askerka et al.,246 in which ammonia binds as a sixth ligand to the Mn4(III) ion of the high-spin closed cubane form of the S2 state, transforming it into a new valence-shifted low-spin form. 9489


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Figure 12. Major scenarios for the S2−S3 transition discussed in the text: binding of second-sphere water to Mn1 (a), binding of Ca-bound water to Mn1 (b1) or Mn4 (b2), and progression to the S3 state without water binding (c). The site of initial deprotonation (W1 or W3) is indicated with B,W B green color. Three possible forms of the S3 state can be produced (SA,W 3 , S3 , and S3 ); even though some scenarios lead to structurally indistinguishable models, the natures of the transition and the origins of the incoming water (indicated with blue arrows) are fundamentally distinct.

closed cubane form becoming the leading conformation. An interesting and complex phenomenology has been reported by Ioannidis and co-workers,198,227,252 who observed two forms of the S2YZ• split signal, a broad one and a narrow one, with distinct temperature dependences of their formation and decay behaviors.198 These two signals were tentatively associated with a two-step mechanism of proton translocation, one step relating to the proton shift from Tyr160 to His190 and the other step to a proton shift from His190 to Asn298.198 This idea needs to be further evaluated because it potentially implies a proton transfer role for the water channel system on the O1 side. Of relevance here is a recent computational study by Kawashima et al.253 that suggests the possibility of rotation of the Asn298 side chain in connection with radical formation at the Tyr160−His190 pair. Calcium is an essential component of the OEC.58,254 Calcium depletion does not induce drastic changes in the geometric and electronic structure of the cluster in the S2 state,255−257 but it inhibits progression to the S3 state.258 It is

structural and chemical differences among representative models. The initiating step in the transition is the oxidation of YZ by P680•+. This leads to an intermediate that can be trapped and studied by EPR spectroscopy. It displays a characteristic “split signal”, where the radical signal of the tyrosyl appears to be split as a result of the interaction with the spin of the Mn cluster.100,101,250,251 Formation of the YZ• state is accompanied by transfer of the phenolic proton to His190. DFT studies of the intermediate187 suggested that both forms of the S2 state, the low-spin open cubane form and the high-spin closed cubane form, can produce the S2YZ• state, with the energy difference between the closed and open cubane forms remaining almost the same as in the S2 state (it should be noted that in the present nomenclature, we reserve the label “S3” exclusively for species in which the inorganic cluster itself is oxidized). On the other hand, simulations by Narzi et al.182 indicated that the relative stability of the two geometric forms is reversed upon formation of the tyrosyl radical, with the 9490


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the closed cubane form of S2).140,194−197 Alternatively, W1 may be deprotonated while a water is shifted as H2O to Mn4.140 The hydroxy shift to Mn1 leads to the same S3 structure as the first model discussed above (SA,W 3 ), since both ideas implicate the open cubane form of the S2 state and result in the oxidized Mn1 becoming sixcoordinate by gaining an OH ligand. However, the sequence of events and the origin of the additional Mn ligand are different. It should be noted that the number of calcium waters can be conserved because the OH shift would be accompanied by the binding of a secondsphere water.140,182 Depending on the structural form of the S2 state and hence the site (Mn1 or Mn4) that is involved, the two possibilities lead to isomeric forms of and SB,W the S3 state (SA,W 3 3 ) that correspond to the open/closed isomers of S2 with a sixth OH ligand at the former Mn(III) ion of each isomer. (c) The third model174,182 involves a gating mechanism because it implicates both forms of the S2 state in the transition. Specifically, it suggests that W1 is deprotonated in the open cubane form but that oxidation by YZ• occurs only in the deprotonated closed cubane S2YZ• species, i.e., at the Mn4(III) site. In other words, the shift from the open to the closed cubane form of the S2 state of the cluster in the presence of the YZ radical leads spontaneously to reduction of YZ•. A crucial point here is that water (or hydroxy) binding is not required for the cluster to be oxidized, and hence, the S2 closed cubane form advances to the S3 state with a five-coordinate Mn4(IV) center.174 This model is shown as SB3 in Figure 12. Therefore, in this scenario water binding can occur after the cluster is alreadyin terms of manganese electronic structurein the S3 state. In all three models for the S2−S3 transition, the result is an all-Mn(IV) cluster, but the binding of a OH group to the internal site of Mn1 represents the direct progression of the open cubane S2 isomer, whereas the binding of a OH group to Mn4 leads to the corresponding S3 alternative of the closed cubane S2 form. The latter model (SB,W 3 ) can be converted to the more stable SA,W form with a one-step transformation.277 It 3 has been suggested that the “carousel” mechanism proposed by Askerka et al. for the binding of ammonia in the S2 state of the OEC (Figure 11) may be analogous to the water binding process in the S2−S3 transition.246,247 In principle, this type of mechanism would also lead to a structure such as SB,W 3 . Finally, the third possibility leads to the intermediate SB3 ,174 essentially the deprotonated and oxidized closed cubane S2 form without addition of any other ligand. The structure differs from the S2 state because the Mn4(IV) site is stabilized by a rotating motion of the two OH groups (W1 and W2) so that it adopts a quasi-trigonal-bipyramidal coordination geometry.174 It is noted that even without any ligand addition, the cluster does not collapse into a more compact form as hypothesized in a particular interpretation of EXAFS data.31 Spectroscopic studies appear to support the advancement of the closed cubane component of S2. For example, Boussac et al.134 observed that in both Ca and Sr PSII, the high-spin form of the S2 state is capable of advancing to S3 at low temperature (198 K), and they suggested this to be an experimental demonstration that the low-spin S2 state advances to S3 via the high-spin S2 state without detectable intermediates. Gates et al.278 similarly concluded that the S = 5/2 form of the S2

suggested to be necessary for effecting the interconversion between the S2 state conformers or to be responsible for regulating the hydrogen-bonding environment and the properties of the cluster or the redox-active Tyr160 residue.144,145,208,259−266 Among other divalent cations, only strontium can replace calcium at the OEC and maintain oxygen evolution, at a lower steady-state rate.254,267,268 The idea of redox potential adjustment is in analogy to observations in synthetic Mn cluster complexes53,54,105,269 that incorporate different redox-inactive cations.53,270−272 In that case, a direct correlation was seen between the Lewis acidity of the cation and the effect on the redox potential of the complex.270,271 However, quantum-chemical modeling of the OEC has shown that these conclusions are not directly transferable to the biological system, where the plasticity of the coordination sphere suppresses the effect of the redox-inactive cation on the redox potential of the Mn core.273 Analysis of the electronic structure of the YZ radical and the role of Ca in structuring its hydrogen-bonding environment suggested instead that calcium is likely responsible for regulating the redox properties of the tyrosyl radical rather than those of the Mn cluster.187 Even though there is a sensitive response in EPR properties,89,153 comparison of calcium and strontium crystallographic models for dark-adapted PSII samples274 or of computational models for the S2 state and possible intermediates of the S2−S3 transition153,275,276 has not revealed substantial differences in terms of geometries, thermodynamics, and kinetics apart from an expected elongation of heterocation bonds.153,275,276 It is conceivable, however, that some important element is missing in the modeling of the Sr-substituted states. Indeed, reactioninduced FTIR spectroscopic studies indicated that Ca2+/Sr2+ substitution is correlated with an alteration of the conformational landscape of the S2−S3 transition.265 In addition, EPR studies suggested a strong effect of strontium on the equilibrium among the various forms of the heterogeneous S2 and S3 states,89 and accompanying DFT studies indicated that Ca2+/Sr2+ substitution modifies the electronic structure of several titratable groups within the active site, even of groups that are not direct ligands to calcium or strontium.134 The multitude of ideas about what might happen after the system reaches the S2YZ• state can be classified into various categories depending on the assumed sequence of events and the proposed involvement of specific metal ions or ligands. For the purposes of this review, we will focus on three types of model (see Figure 12) that are being currently considered: (a) The first model was advanced by Siegbahn,188 who suggested that after oxidation of YZ by P680•+, the W1 ligand to Mn4 in the open cubane form of S2 loses a proton to the lumen. Subsequently Mn1, the Mn(III) ion of the core, is oxidized to Mn(IV) and can bind a sixth ligand. This is provided by a second-sphere spectator water (Wx). This water is deprotonated through a proton relay that eventually results in reprotonation of W1 to H2O, while the newly formed OH binds to the open coordination site of Mn1. The in Figure resulting model of the S3 state is shown as SA,W 3 12 to indicate that it is structurally related to the open cubane structure (SA2 ) and involves water association. (b) The second model involves initial deprotonation of a calcium-bound water (W3). Then the formed OH is shifted to the formally available coordination site of either Mn1 (in the open cubane form of S2) or Mn4 (in 9491


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Figure 13. Suggested mechanism for water binding at the five-coordinate Mn4(IV) component of the S3 state (SB3 ).174 Ligands other than those directly implicated are not shown. Regardless of the details of the S2−S3 transition and the water delivery step (i.e., whether or not the S2−S3 transition actually involves formation of the SB3 intermediate), interconversion among all three models of the S3 state discussed here is possible.174,277

shown in Figure 12. However, the relatively wide equatorial O4−Mn4−W1(OH) angle of this species suggests that the former W1 site is available for water binding. Indeed, a lowbarrier transition state was computed for the binding of the end-point water of channel A to the five-coordinate Mn4, with the other groups pivoting toward O5 (described in the literature as the pivot mechanism for water binding; Figure 13).174 The result of this water addition is structurally equivalent to the model resulting from OH addition to the internal site of the Mn4 ion discussed above (model SB,W 3 ), but the origin of the groups and all of the steps of the process leading to this structure are fundamentally different. The fact that this “pivot” mechanism for water binding externally at the Mn4 ion of SB3 implicates channel A is an advantage because this specific channel was identified as the one through which the substrate analogues methanol and ammonia reach the OEC (see above, Figures 9−11), and hence, it is reasonable to expect that water approaches the OEC from the same pathway. It is noted that the “carousel” mechanism suggested by Askerka et al.246,247 would involve the same delivery pathway, but the available descriptions of the mechanism (no explicit calculations have been presented to date to support this idea explicitly in the case of water) appear to suggest that water binding is expected to precede Mn oxidation, in contrast with the requirement for prior Mn oxidation and formation of the SB3 state described by Retegan et al.174 In terms of computed energetics, binding of an external water to the “outer” side of Mn4 was shown to be more favorable than the binding of a Cabound water to the internal sites of either Mn1 or Mn4.174,283 The properties of the three individual S3 models will be discussed in the following section. The above brief exposition provides a qualitative description of the main ideas regarding structural aspects of the S2−S3 transition. Further work is required to identify intermediates, sites and pathways of deprotonation, and water delivery points, all of which are crucial for confirming the identities of the groups that will form the O−O bond and for clarifying whether the water that binds in the S3 state is a substrate of the running cycle.

state, the form stabilized by strontium substitution, is the active form in the catalytic cycle relative to the low-spin S = 1/2 form. All of the models require the loss of a proton to precede or be coupled with subsequent geometric and electronic changes. Therefore, all can be considered broadly consistent with a range of experimental studies that identify distinct kinetic phases in the transition, the first (after a fast structural change that accompanies YZ• formation)279 most probably related to a deprotonation event.28,122,280,281 On the other hand, the three models involve distinct deprotonation sites, and the likelihood of each would depend on the acidity of each group and the availability of proton relay pathways. W1 is a likely deprotonation site because it was computed to be the most acidic group in the cluster both by static proton binding energy calculations174 and in ab initio molecular dynamics simulations.182 The deprotonation may be triggered by reorientation of the dipole moment of the OEC along the Mn4−W1− Asp61 direction upon formation of the tyrosyl radical187 and proceeds via the direct acceptor Asp61, which can subsequently alter its conformation to enable further proton transfer.182,183 Deprotonation of a Ca-bound water is also plausible, but although the consequences of this hypothesis have been explored, to date no evidence is available to support the idea that the Ca-bound waters are more acidic than the Mn4(IV) ligands. However, it should be recognized that the problem of computing relative acidities for groups that are embedded in hydrogen-bonding networks does not have a straightforward computational solution. A second consideration relates to the presence of an acceptor and a suitable proton transfer pathway. In the case of W1, these are Asp6136,51,121,158,175,182−184,188,282 and channel B,175 possibly facilitated by the proximal chloride. In the case of W3, these are not obvious, but the possibility of involvement of His190 and/or Asn298 can be considered.274 A related point is which type of deprotonation would open the way for oxidation of the Mn(III) ion by the tyrosyl radical. Both intuitively and on the basis of calculations,174 deprotonation of a Mn-bound water would directly affect the redox potential of the metal, whereas deprotonation of a Ca-bound water would not. A further significant difference between the scenarios for the S2−S3 transition is the water delivery channel. For the first mechanism, the assignment of a channel is not obvious because the Wx that is suggested to bind to Mn1 does not appear to belong to one of the readily identifiable channel systems. The mechanism involving Ca assumes water delivery from channel system C. Binding of a sixth ligand to the five-coordinate Mn4(IV) ion of the SB3 form can proceed in a number of ways, including internally via Ca as a variation of the b2 mechanism

9. THE S3 STATE 9.1. Properties of Possible Structural Components. In the preceding section, three possible forms of the S3 state were discussed. Other models have been proposed for the S3 state that involve chemical and redox equilibria284 or ligand-based oxidation to form a terminal Mn−oxyl radical.21,183,285 Although we acknowledge their possible relevance for understanding higher-energy forms of the S3 state284 or water exchange processes,282 here we will cover only the three models discussed above because they are the most 9492


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This is the consequence of the coordination geometry of Mn4 that suppresses superexchange over the O4 bridge, resulting in weak ferromagnetic coupling between the high-spin cubane subunit and the pendant Mn4. The properties of this structure provide straightforward explanations for a series of experimental observations. Specifically, the S3 state is spectroscopically heterogeneous89 and contains a form with spin S = 3 that is detectable by EPR spectroscopy and not sensitive to nearinfrared light (this could presumably correspond to the SA,W 3 species discussed above) and also a form that is not visible in the EPR spectrum but in which the Mn cluster absorbs in the near-infrared, resulting in formation of a modified (S2YZ•)′ split EPR signal. Neither the absence of an EPR signal nor the NIR absorption (assuming that this arises from a spin-allowed d−d transition) can be explained by S3 state models with octahedrally coordinated Mn(IV) ions. However, both can be explained by the SB3 species because of the properties arising from the trigonal-bipyramidal Mn4(IV) site. The Mn4 center was computed to have a large positive local zero-field splitting (computed D > 2.1 cm−1 by the local complete active space configuration interaction method),293 which agrees with the zero-field splitting reported for synthetic five-coordinate mononuclear manganese complexes by Borovik.294 This might be related to the inability to observe an EPR signal at certain frequencies, although clarification of this requires further studies. Importantly, the trigonal-bipyramidal geometry of the high-spin d3 ion results in an orbital splitting (Figure 14) in which the highest occupied and lowest

consistent with the conclusions of X-ray and EPR spectroscopies, which exclude early onset of water oxidation and show all of the Mn ions to be present as Mn(IV). Crucially, regardless of their formation pathway, the three forms are interconvertible.174,194,277,286 This means that in principle they can all contribute as components of the S3 state irrespective of which S2−S3 transition scenario turns out to be closer to reality. Indeed, spectroscopic heterogeneity is well-established from EPR studies of the S3 state, as revealed particularly through chemical and structural perturbations or from responses to specific radiation wavelengths.89 The S3 model SA,W that bears an extra OH on Mn1 3 compared with the open cubane SA2 component is the one that currently has the strongest support. This has been the subject of several computational studies and implicated in the water oxidation mechanism proposed by Siegbahn,121 where it is assumed that the Mn1-bound OH and the O5 bridge are the substrates in O−O bond formation. This type of structure is suggested to be consistent with the EXAFS of the S 3 state,287,288 but it should be noted that the ability to reliably or uniquely predict EXAFS spectra from first principles is extremely limited for such a complex structure.289 It is clear from the literature that simulated EXAFS is a poor discriminative criterion, as a model with an incorrect stoichiometry and structure as well as a model consistent with the more recent Umena XRD structure could both be shown to agree with the experimental EXAFS.61,290 The model comes from magnetic strongest support for the SA,W 3 resonance spectroscopies, which established291 the presence of a species with a total spin of S = 3 in which all of the Mn ions are isotropic and electronically similar13 and hence Mn(IV) and octahedrally coordinated. Computational studies compared various structural models against these data and concluded that the SA,W model best corresponds to the EPR 3 observations because it reproduces the experimentally observed type and distribution of manganese hyperfine couplings.13,56,292 The presence of Mn(III) ions would lead to models that are incompatible with the experimental data.56 The isomeric form SB,W that contains a closed cubane 2 Mn3CaO4 unit and has the extra OH group at Mn4 is 13,56,277 This type of computed to be less stable than SA,W 3 . structure also has a ground-state spin of S = 3 and therefore could also be associated with the observed EPR signal, but the computed 55Mn hyperfine coupling constants reproduce less well the experimental distinction into two large and two small there is a weakly coupled couplings.13,56 Specifically, in SA,W 3 ferromagnetic Mn1−Mn2 subunit (S12 = 3) and a weakly coupled antiferromagnetic Mn3−Mn4 subunit (S34 = 0), leading to two classes of spin projections, large for Mn1−Mn2 and small for Mn3−Mn4.56 By contrast, in the trimer− 9 monomer topology of SB,W 3 , where the S = /2 cubane couples antiferromagnetically with the outer Mn4, the spin projection coefficients are approximately equal, leading to similar hyperfine coupling constants for all of the sites.56 At present there is not enough evidence to conclude with confidence whether this alternative isomer can be identified with some of the existing spectroscopic observations.89 The third proposed component (but possibly the first to be formed upon Mn oxidation in the S2−S3 transition)174 is the intermediate S3B, which is suggested to contain a fivecoordinate Mn4(IV) site. In contrast to the other two structures discussed above, the computed spin state of this species is S = 6, i.e., the highest possible for four Mn(IV) ions.

Figure 14. Orbitals of the SB3 structure centered at the five-coordinate Mn4(IV) site, showing idealized symmetry labels and the transition that is responsible for the absorption in the near-infrared. Adapted from ref 174, published by The Royal Society of Chemistry.

unoccupied Mn4-based d orbitals (dyz and dz2) have a small energy separation and the corresponding excitation (4A1 → 4 B2) falls in the NIR region, as confirmed by both timedependent DFT and multireference calculations.174 The highest affordable methodological level, N-electron valence perturbation theory (NEVPT2) applied on top of a CASSCF(12e,20o) wave function, led to a value of 735 nm for the lowest-energy excitation,174 in close agreement with the experimentally observed absorption maximum of ca. 740− 760 nm.295,296 Presumably the creation of a Mn4-based hole by this initial event leads to oxidation of YZ and the formation of a species with approximately the bonding topology and Mn 9493


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ACS Catalysis oxidation state distribution (IV−IV−IV−III) of a deprotonated closed cubane S2-like form. A recent study utilizing variable-temperature variable-field (VTVH) magnetic circular dichroism (MCD) suggested an alternative origin of the nearinfrared absorption for all S states, namely, a 4A → 2E spin-flip excitation at a d3 Mn(IV) site instead of a d−d excitation.297 This type of excitation has not been considered in existing theoretical studies, and the suggestion will need to be carefully evaluated. Regardless of the electronic nature of the initial absorption event, a crucial observation is that the tyrosyl EPR signal formed as a result (the modified S2YZ• signal) is split by a form of the manganese cluster that carries a spin S ≥ 5/2, implying that the manganese cluster contains a closed Mn(IV)3CaO4 cubane subunit and hence supporting the assignment of the NIR absorption to an S3 component that already contains a closed Mn(IV)3CaO4 subunit, i.e., SB,W or the non-water3 . Experimental observation of an bound species SB3 but not SA,W 3 intermediate with a five-coordinate Mn center would lend strong support to the associated scenario for the S2−S3 transition and to the idea that water binding is decoupled from Mn oxidation.174 This would in turn support the notion proposed on the basis of substrate exchange kinetics that both substrates are already bound in the S2 state and hence that the water that binds in the S3 state is not a substrate.298 To probe the formation of the five-coordinate species, it would be necessary to inhibit water delivery in this transition. A likely way to achieve this would be to use methanol-treated PSII from higher plants, where methanol was suggested to occupy the end point of the O4-terminating channel.148,149 9.2. Assessment of Crystallographic Models. An important recent development is the application of XFEL techniques to the structural elucidation of the S3 state, but for the moment these studies must be considered exploratory. A study by Young et al.22 did not report significant structural changes in the S3 state compared to the S2 state, but Brudvig and co-workers highlighted significant issues with the data processing and interpretation.299 A computational study also showed that the proposed model is inconsistent with the electronic structure of the S3 state of the OEC.300 More recently, Suga et al.23 reported a model for the two-flashed state at nominal 2.25 Å resolution that was suggested to show the binding of a sixth oxygen ligand in the central region of the cluster (Figure 15). From a cursory observation of the topology of the Mn4CaO6 model it might be tempting to identify similarities with the discussed above (Figure 12). computational model SA,W 3 However, closer inspection of the structural parameters shows this to be untenable. The crystallographic model contains three short Mn−Mn distances, in rough qualitative agreement with EXAFS for the S3 state, but the Mn−O distances are too long by ca. 0.3 Å on average to be considered consistent with the Mn(IV)4 state of the OEC. The distances between Mn4 and the water-derived ligand at the W1 position and between Mn4 and O5, as well as the Mn1−O6 and Mn1− Asp342 distances, are at best consistent with Mn(III) Jahn− Teller elongations along this direction and lie way outside any plausible limits for bonds between Mn(IV) and oxygen groups. The distinctive feature is a close O−O contact of less than 1.5 Å between O5 and O6. If this is considered a genuine structural feature, it can only be interpreted as an O−O bond. This distance is in no way compatible with a hydrogen bond because this would require an O−O separation greater than 2.4

Figure 15. Model of the S3 state proposed on the basis of the femtosecond XFEL study by Suga et al.23 Selected distances (in Å) are shown.

Å. Consequently, an interpretation of the Suga et al. structure as indicative of the inclusion of an OH group (as O6) does not follow from the data. Taken at face value, the Mn−O distances and the O−O bond length would be consistent with reduced Mn ions and peroxide formation. Indeed, a computational model based on the “low oxidation state scheme” (i.e., containing two Mn(III) centers) was suggested to provide a good fit.301 However, the presence of Mn(III) ions in the S3 state has been ruled out on the basis of various spectroscopic results13,17,302 as well as substrate exchange kinetics303−305 that precludes early onset of water oxidation and Mn reduction in the S3 state. Indications of anomalies can be found in the incompatibility between the FTIR-based quantification of the S3 state (less than 50%) and the percentage assumed in the modeling (80%), the failure to model the dark-stable S1 state itself without the imposition of restraints from older structures, and the inconsistent occupancies of O5 and O6. For the latter, the occupancy is much less than what would be expected if the model actually reflected the S3 state. A literal interpretation of the 2.25 Å XFEL model is therefore implausible, and an alternative explanation must be sought. Heterogeneity in the S3 state, as implied by spectroscopy, would impact the nature of medium-resolution crystallographic models, which necessarily reflect an unresolved superposition of all forms and conformations present in a given catalytic state. A superand SB,W models discussed position of forms such as the SA,W 3 3 above may explain the apparent short O−O distance. On the other hand, it is unlikely to explain the abnormally long Mn−O distances in the model, which may result from incomplete elimination of the contribution of lower-oxidation-state components. In conclusion, the existing S3 crystallographic models should be viewed as preliminary. Future improvements in this direction will certainly result in more reliable models, but it is clear that these studies cannot be meaningfully evaluated if the interpretations ignore the information on the electronic structure of the S3 state derived from EPR and X-ray spectroscopies. 9494


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structural rearrangement321 or deprotonation event after S3YZ• formation but before oxidation of the manganese cluster.122,322−324 However, these observations cannot be directly related to any specific mechanistic scenario, and it is hard to regard them as constraints in the elaboration of hypothetical models. In 1999 Siegbahn and Crabtree325 implicated a terminal Mn(IV)−O• oxyl group, a species originally described and discussed by Yamaguchi,326 in a mechanism that involved attack of an external water to form a Mn−OOH intermediate in the S3 state. Although the structural model and the details of that work in the context of the current understanding of the OEC are obsolete, the manganese−oxyl idea has survived in later studies and remains a feature of most subsequent computational variations. According to one of the current formulations of this idea,121 the Mn1−OH group of the SA,W 3 species is deprotonated and oxidized in S4, forming a terminal Mn1(IV)−oxyl. The O−O bond is subsequently formed by coupling of this radical with the proximal O bridge that is bound to Mn1 and Mn3. In this context, a spin alignment requirement has been pointed out,43 according to which the terminal Mn ions and the two O atoms that couple should adopt an alternating orientation of local spins to ensure lowbarrier bond formation. The resulting peroxide bridges Mn1 and Mn3, while Mn4 is reduced to Mn(III). The two Mn ions subsequently accept one electron each, resetting the cluster to the III−IV−III−III (S0) oxidation states and releasing O2.121 The coupling of a terminal Mn(IV)−oxyl radical and a bridging oxo group has also been suggested for synthetic Mnbased water oxidation catalysts.327,328 It should be clarified that the above coupling scenario described by Siegbahn does not require the associated S2−S3 progression proposed by the same author because the same type of model for the S3 and S4 states can arise through different pathways (see above). Indeed, the original identification of substrates by Siegbahn is problematic because the proposed binding of an external water to Mn1 is neither energetically favorable174,283 nor compatible with the observed substrate exchange kinetics in the S2 and S3 states.298 Nevertheless, it is noted that the O5 bridge in the S2 state has been supported to be one of the substrates using EPR-detected NMR spectroscopies.155,329 Shoji et al.330 proposed a variation of the above progression that implicates nonadiabatic one-electron transfer. This component of the S3 mechanism proceeds also from the SA,W 3 state. However, upon formation of S3YZ•, an internal proton transfer from the Mn1−OH group to the Mn4-bound W2/OH occurs, mediated by the Ca-bound W3, while the Mn4 ion is reduced to Mn(III) by the emergent Mn1−oxo/oxyl moiety. The latter interacts with the O5 bridge, forming an incipient “one-electron” O−O bond (formally O23−) that becomes a peroxidic unit bridging the Mn1 and Mn3 ions with concomitant reduction of the tyrosyl radical. Importantly, this mechanism involves ferromagnetic alignment of all of the Mn spins, in contrast to the mechanism described above. This enables the same high-spin state of the Mn cluster to be maintained throughout the O−O bond formation, the transfer of same-spin π* electrons from the peroxide bridge to Mn1 and Mn3, and the direct formation of triplet dioxygen. The same spin considerations, requiring a high spin state of the cluster, were supported independently by Jiao et al.331 An alternative hypothesis involves catalytic advancement of structure, leading to a Mn(IV)−O• group at the Mn4 the SB,W 3 site. This radical can analogously couple with the O5 bridge or

10. ADVANCEMENT TO THE S4 STATE AND O−O BOND FORMATION As discussed in the context of the S2−S3 transition, all three A,W species SB3 , SB,W (Figures 12 and 13) may contribute 3 , and S3 to the “S3 state”, and these models may not even exhaust all of the possibilities.183,284 It is unlikely that any current experimental data set contains sufficient information to distinguish among such closely related components, and therefore, it is reasonable to consider all of these species as candidates for advancement to the S4 state. The S3YZ• intermediate resulting from light-driven tyrosine oxidation can be trapped, and its EPR spectrum100 was successfully modeled with a dipolar interaction between the tyrosine spin of S = 1/2 and a spin of S = 9/2, presumably corresponding to the cuboidal trimeric subunit of the OEC antiferromagnetically coupled to a third spin of S = 3/2, presumably that of the terminal Mn4 ion.306 This result may not be sufficiently restrictive, but it is more consistent with the “closed cubane” model SB,W because the exchange coupling constants13,56 3 support an effective description of the cluster as a pair of two antiferromagnetically coupled trimer−monomer spins (S = 9/2 and S = 3/2), whereas the magnetic topology of the “open” model SA,W is consistent with a dimer of dimers description (S 3 = 3 and S = 0), which justifies the 55Mn hyperfine coupling distribution.13 An important observation is that substrate water exchange is arrested upon tyrosine oxidation.307 It has been suggested that substrate exchange requires a Mn(III) ion within the cluster,282 which can be formed by internal electron transfer from the reduced tyrosine. In the S3YZ• intermediate, the tyrosine has already lost an electron, and no electron donor is available to form a Mn(III) ion. Hence, substrate exchange is arrested. An additional consideration would be that the experimental observations refer to an unprotonated form of the cluster, in which case the absence of exchange is instead attributable to much stronger binding of the deprotonated group or to the impossibility of exchange-enabling proton tautomerization. The final oxidation could be either metal- or ligand/ substrate-centered. This relates to the question of how many metal-centered charging events precede O−O bond formation, that is, whether there are only three holes that need to be filled upon reaching the S4 state or instead the charging phase of the cycle involves genuine four-hole accumulation. This would also determine the nature of the “hot” species and the possible ways of forming the O−O bond, leading to odd-electron or evenelectron chemistry. The latter (four-electron or two-electron transformation) is in principle favored thermodynamically.308 The two ideas that have been discussed historically are the formation of a high-valent Mn(V)−oxo species or a Mn(IV)− oxyl radical in the S4 state. The former is associated with acid− base O−O bond formation via nucleophilic attack to the terminal oxo of an external water or another Mn- or Ca-bound H2O/OH group, while the latter is associated with radical-type chemistry. The electronic structure details of these mechanisms are obviously relevant not only for dioxygen formation in the biological system but also for synthetic Mn-based catalysts.5,7,105,309−311 The subject of O−O bond formation in the OEC has provided fertile ground for numerous and divergent “pen-andpaper” ideas as well as for computationally traced mechanisms.40,312−320 Only a few representative models can be discussed here. Experimental studies to date have supported a 9495


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Figure 16. Selected representative models for the final catalytic step of the OEC. (a) The oxo−oxyl coupling mechanism described by Siegbahn121 with formation of a Mn(IV)−oxyl group on Mn1 and an alternating spin arrangement. (b) The first step of the nonadiabatic one-electron transfer mechanism described by Shoji et al.330 with a ferromagnetic spin arrangement. (c) Formation of a Mn(IV)−oxyl radical on the Mn4 center, mirroring the first scenario. (d) Hypothetical S4 state model containing a five-coordinate Mn(V)−oxo site.

required to release O2 and reset the system to S0.121 This was suggested to involve initial release of peroxide with a large entropy gain, accompanied by reduction of two Mn(IV) ions to Mn(III). The release of O2 is endergonic and is followed by movement of a Ca-bound water to the center of the cluster, which is coupled to deprotonation and a series of intermediate proton transfers toward a Mn4-bound hydroxide before a new water molecule binds to calcium.121 The highest barrier for this process was estimated at 14.0 kcal mol−1 with respect to the S3 state, which is higher than the estimated barrier for O−O bond formation itself according to this mechanism (11.3 kcal mol−1).121 Li and Siegbahn318 later revisited these models for O−O bond formation and O2 release and suggested structural variations that placed the estimated barrier for both O2 formation and the S0 reconstitution step at ca. 11 kcal mol−1, still leaving open the possibility that dioxygen release, rather than O−O bond formation, might be the overall rate-limiting step. The S4−S0 transition was also studied computationally by Shoji et al.,335 who presented a concerted mechanism of water insertion and O2 release. This mechanism also involves several steps, with O2 being detached one atom at a time from the Mn cluster before it migrates to a hydrophobic space surrounded by Val185 and His332 while a Ca-bound water (W3) enters the position left vacant by the departing O2. The concerted O2 release/W3 insertion step was reported to have the highest activation free energy barrier in this process (10.4 kcal mol−1) and leads to a “pre-S0” state that converts to S0 proper by proton translocation to the OH ligand at the W2 position.335 Shoji et al. emphasize the importance of the Val185−His332 pair as defining the entrance point of an O2 release channel.335 In these studies, Ca2+ plays the crucial role of directing the delivery of the water molecule that will be incorporated into the cluster as the O5 bridge and may serve as one of the substrates in the next cycle. Independent evaluation of such

be attacked by a Ca-bound H2O/OH group in a way similar to that described in early QM/MM studies by Batista and coworkers.44 Despite using the nomenclature of nucleophilic attack, these studies had also provided clear support for oxyl radical formation.44 The mechanism involving attack of a nucleophile was, however, disfavored by Siegbahn on the basis of computed energies.332 For completeness, a model is shown in Figure 16 that involves advancement of the non-water-bound SB3 form174 to the S4 state. In this scenario, a terminal oxo would be formed at the five-coordinate Mn4 site. It is unclear whether this group would have radical character. Synthetic complexes with a fivecoordinate Mn(V) ion are locally high-spin and have significant covalency-induced spin density on the axial oxygen group.294,333 An S4 species with a trigonal-bipyramidal Mn4(V) would also be locally high-spin, but the radical character on the oxygen might be suppressed in the equatorial position. If that is the case, then this species would be the only conceivable formulation of a “genuine” Mn(V)−oxo species, since otherwise an octahedrally coordinated Mn site favors the Mn(IV)−oxyl as opposed to the Mn(V)−oxo formulation, in which the two Mn electrons would have to be paired in the nonbonding dxy orbital. This preference has also been reported and analyzed for terminal Mn−O groups in octahedral environments at lower oxidation states of the metal.334 As such, a five-coordinate Mn(V)−oxo site could possibly enable a “genuine” intramolecular nucleophilic coupling for O−O bond formation (e.g., between the Mn(V)−oxo unit and the O5 bridge; see Figure 16d) that might be synchronized with, or aided by, binding of a loosely associated incoming water (Figure 13) trans to the newly formed O−O moiety. In his computational studies on the mechanism of water oxidation, Siegbahn pointed out that after formation of the O− O bond in the S4 state a complicated sequence of steps is 9496


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(2) Messinger, J.; Renger, G. Chapter 17: Photosynthetic Water Splitting. In Primary Processes of Photosynthesis, Part 2: Principles and Apparatus; Renger, G., Ed.; Comprehensive Series in Photochemistry and Photobiology, Vol. 9; Royal Society of Chemistry: Cambridge, U.K., 2008; pp 291−349. (3) Krewald, V.; Retegan, M.; Pantazis, D. A. Principles of Natural Photosynthesis. Top. Curr. Chem. 2015, 371, 23−48. (4) Dau, H.; Zaharieva, I. Principles, Efficiency, and Blueprint Character of Solar-Energy Conversion in Photosynthetic Water Oxidation. Acc. Chem. Res. 2009, 42, 1861−1870. (5) Najafpour, M. M.; Renger, G.; Hołyńska, M.; Moghaddam, A. N.; Aro, E.-M.; Carpentier, R.; Nishihara, H.; Eaton-Rye, J. J.; Shen, J.-R.; Allakhverdiev, S. I. Manganese Compounds as Water-Oxidizing Catalysts: From the Natural Water-Oxidizing Complex to Nanosized Manganese Oxide Structures. Chem. Rev. 2016, 116, 2886−2936. (6) Blakemore, J. D.; Crabtree, R. H.; Brudvig, G. W. Molecular Catalysts for Water Oxidation. Chem. Rev. 2015, 115, 12974−3005. (7) Kurz, P. Biomimetic Water-Oxidation Catalysts: Manganese Oxides. Top. Curr. Chem. 2015, 371, 49−72. (8) Umena, Y.; Kawakami, K.; Shen, J.-R.; Kamiya, N. Crystal Structure of the Oxygen-Evolving Photosystem II at a Resolution of 1.9 Å. Nature 2011, 473, 55−60. (9) Cardona, T.; Sedoud, A.; Cox, N.; Rutherford, A. W. Charge Separation in Photosystem II: A Comparative and Evolutionary Overview. Biochim. Biophys. Acta, Bioenerg. 2012, 1817, 26−43. (10) Rutherford, A. W.; Osyczka, A.; Rappaport, F. Back-Reactions, Short-Circuits, Leaks and Other Energy Wasteful Reactions in Biological Electron Transfer: Redox Tuning to Survive Life in O2. FEBS Lett. 2012, 586, 603−616. (11) Joliot, P.; Barbieri, G.; Chabaud, R. Un Nouveau Modele Des Centres Photochimiques Du Systeme II. Photochem. Photobiol. 1969, 10, 309−329. (12) Kok, B.; Forbush, B.; McGloin, M. Cooperation of Charges in Photosynthetic O2 Evolution − I. A Linear Four Step Mechanism. Photochem. Photobiol. 1970, 11, 457−475. (13) Cox, N.; Retegan, M.; Neese, F.; Pantazis, D. A.; Boussac, A.; Lubitz, W. Electronic Structure of the Oxygen-Evolving Complex in Photosystem II Prior to O-O Bond Formation. Science 2014, 345, 804−808. (14) Iuzzolino, L.; Dittmer, J.; Dörner, W.; Meyer-Klaucke, W.; Dau, H. X-ray Absorption Spectroscopy on Layered Photosystem II Membrane Particles Suggests Manganese-Centered Oxidation of the Oxygen-Evolving Complex for the S0-S1, S1-S2, and S2-S3 Transitions of the Water Oxidation Cycle. Biochemistry 1998, 37, 17112−17119. (15) Dau, H.; Liebisch, P.; Haumann, M. X-ray Absorption Spectroscopy to Analyze Nuclear Geometry and Electronic Structure of Biological Metal CentersPotential and Questions Examined with Special Focus on the Tetra-Nuclear Manganese Complex of Oxygenic Photosynthesis. Anal. Bioanal. Chem. 2003, 376, 562−583. (16) Haumann, M.; Müller, C.; Liebisch, P.; Iuzzolino, L.; Dittmer, J.; Grabolle, M.; Neisius, T.; Meyer-Klaucke, W.; Dau, H. Structural and Oxidation State Changes of the Photosystem II Manganese Complex in Four Transitions of the Water Oxidation Cycle (S0 → S1, S1 → S2, S2 → S3, and S3,4 → S0) Characterized by X-ray Absorption Spectroscopy at 20 K and Room Temperature. Biochemistry 2005, 44, 1894−1908. (17) Zaharieva, I.; Chernev, P.; Berggren, G.; Anderlund, M.; Styring, S.; Dau, H.; Haumann, M. Room-Temperature EnergySampling Kβ X-ray Emission Spectroscopy of the Mn4Ca Complex of Photosynthesis Reveals Three Manganese-Centered Oxidation Steps and Suggests a Coordination Change Prior to O2 Formation. Biochemistry 2016, 55, 4197−4211. (18) Ono, T.-a.; Noguchi, T.; Inoue, Y.; Kusunoki, M.; Matsushita, T.; Oyanagi, H. X-ray Detection of the Period-Four Cycling of the Manganese Cluster in Photosynthetic Water Oxidizing Enzyme. Science 1992, 258, 1335−1337. (19) Kusunoki, M.; Ono, T.; Noguchi, T.; Inoue, Y.; Oyanagi, H. Manganese K-Edge X-ray Absorption Spectra of the Cyclic S-States in

models is impossible given the absence of experimental information on the S4−S0 transition. Characterization of intermediates after Mn reduction but prior to complete reconstitution of the S0 state or studies that would point toward specific pathways of water delivery and dioxygen release would be crucial for clarifying our view and guiding our thinking about this step.

11. CONCLUDING REMARKS The present review, which is necessarily selective in its scope, has aimed to present open questions and points of contention related to structural features of the OEC. Inextricably coupled to these are debates regarding the role and importance of structural heterogeneity, the sequence of oxidation, deprotonation, and water binding in the S2−S3 transition, and the functional role of the immediate environment of the cluster in enabling and controlling the catalytically relevant processes. The history of crystallographic refinements of the OEC teaches the important lesson that no structural model is ever the “whole story”. Spectroscopic methods, particularly magnetic resonance techniques, reveal a more rich and complex picture. This can be resolved to some extent through quantumchemical approaches that use crystallography as starting point but further move toward consistency with orthogonal sources of electronic structure information. A major task therefore remains to construct a coherent, inclusive, and self-consistent model that rationalizes structurally as much information from diverse sources as possible. The answers to open questions regarding the S2−S3 transition and the nature of the S3 state will have a direct impact on possible extrapolations toward the unobserved set of transient intermediates that constitute the multicomponent S3YZ•−S0 transition. Future advances might enable the collection of experimental information on the electronic structure of reactive intermediates. For example, EPR spectroscopy could identify the magnitude and sign of the spin density associated with the terminal oxygen species involved in O−O bond formation, while X-ray spectroscopy might be able to differentiate between metal-based and ligandbased oxidation past the S3YZ• intermediate. This type of information would provide the best constraints for the development of quantum-chemical models. For the moment, it appears that the safest way to approach the problem of distinguishing among the various mechanistic possibilities remains to understand the properties of the preceding observable states and their structural basis, a task that is still unfolding at the forefront of current research.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Dimitrios A. Pantazis: 0000-0002-2146-9065 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS The Max Planck Society is gratefully acknowledged for funding. REFERENCES

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ACS Catalysis

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Missing Pieces in the Puzzle of Biological Water Oxidation - ACS

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