Strong Coupling between the Hydrogen Bonding Environment and

Article pubs.acs.org/JPCB

Strong Coupling between the Hydrogen Bonding Environment and Redox Chemistry during the S2 to S3 Transition in the OxygenEvolving Complex of Photosystem II Hiroshi Isobe,*,†,‡ Mitsuo Shoji,§ Jian-Ren Shen,† and Kizashi Yamaguchi‡,∥ †

Photosynthesis Research Center, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan ‡ The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan § Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan ∥ Institute for NanoScience Design, Osaka University, Toyonaka, Osaka 560-0043, Japan S Supporting Information *

ABSTRACT: We have studied the early phase of the S2 → S3 transition in the oxygen-evolving complex (OEC) of photosystem II using the hybrid density functional theory with a quantum mechanical model composed of 338−341 atoms. Special attention is given to the vital role of water molecules in the vicinity of the Mn4CaO5 core. Our results demonstrate how important the dynamic behavior of surrounding water molecules is in mediating critical chemical transformations such as binding and deprotonation of substrates and hydration of the catalytic site and identify a strong coupling of water-chain relocation near the redox-active tyrosine residue Tyr161 (TyrZ) with oxidation of the Mn4CaO5 cluster by TyrZ•+. The oxidation reaction is further promoted when the catalytic site is more solvated by water. These results indicate the importance of surrounding water molecules in biological catalysts as they ultimately lead to effective catalytic function and/or favorable electron-transfer dynamics.

1. INTRODUCTION Atmospheric oxygenation and evolution of aerobic life on our earth are a result of water oxidation by oxygenic photosynthesis in plants, algae, and cyanobacteria. Photosystem II (PSII) is a pigment−protein complex that initiates light-driven electron transport in the oxygenic photosynthesis.1 The oxygen-evolving complex (OEC) embedded in PSII is the heart of the photosynthetic apparatus and provides all electrons required to reduce NADP+ to NADPH by splitting water into dioxygen and proton.2−5 X-ray diffraction (XRD) experiments have provided a series of sequentially improved models of PSII,6,7 and more recently, a resolution of 1.9 Å was achieved for its dark stable state,8,9 which revealed the detailed structure of the OEC consisting of four manganese and one calcium ion connected by five μ-oxo and/or μ-hydroxo bridges (Mn4CaO5), as depicted in Figure 1. Moreover, the positions of many water molecules were resolved in the vicinity of the Mn4CaO5 core, among which four were coordinated to the Mn4CaO5 cluster directly whereas the others formed extensive hydrogen-bond networks surrounding the Mn4CaO5 cluster. One such hydrogen-bond network was formed via Tyr161 (TyrZ or YZ), which may serve as channels for proton exit or water inlet between the OEC and the internal side of the thylakoid (lumen). The overall topology of the Mn4CaO5 core and its immediate ligand environment were further refined by a recent X-ray free-electron laser (XFEL) study.10 © XXXX American Chemical Society

To achieve four-electron oxidation of water to dioxygen, the OEC periodically stores up to four oxidizing equivalents through five redox states denoted by Si (i = 0−4), in which i represents the number of accumulated oxidizing equivalents.11 Photoexcitation of PSII at the P680 reaction center is coupled to one-electron oxidation of the Mn4 complex via a specific redox-active tyrosine residue TyrZ. There is a consensus that the S0 → S1 and S1 → S2 transitions are Mn-centered oxidations, and the generally accepted oxidation states are MnIII3MnIV for S0, MnIII2MnIV2 for S1, and MnIIIMnIV3 for S2. The mechanism by which the OEC advances to the S3 state has been a subject of extensive discussions and controversy.12−46 A recent high-resolution pulse EPR measurement detected a wellresolved signal at g ≈ 2 in the S3 state,22 which was interpreted as evidence for the S = 3 spin system, consistent with a MnIV4 oxidation state and therefore implying a Mn-centered oxidation also during S2 → S3 transition. It has been suggested from several independent approaches that the Mn4CaO5 cluster undergoes notable structural reorganizations during the S2 → S3 transitions.17,19−21 Renger et al. determined activation and Special Issue: Wolfgang Lubitz Festschrift Received: June 16, 2015 Revised: September 25, 2015

A

DOI: 10.1021/acs.jpcb.5b05740 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry B

Figure 1. A 1.9 Å resolution crystal structure of PSII with cofactors related to photoinduced charge separation being highlighted.8 Water splitting is catalyzed by an inorganic Mn4CaO5 cluster, which exhibits two conformational isomers (open and closed cubanes) in the S2 and S3 states.38,46

Figure 2. QM model (total 338−341 atoms) of the OEC in PSII considered in the present study.

reorganization energies for the redox steps SiYZ•+ → Si+1YZ by fitting available experimental data to the Marcus equation for nonadiabatic electron transfer (ET).23 This analysis showed that the free energies of activation and reorganization for the S2 → S3 transition (36.0 kJ mol−1 and 1.2 eV) are the highest of all S-state transitions and are approximately 3 times of those for the S1 → S2 transition (12.0 kJ mol−1 and 0.41 eV).23 A substrate water molecule presumably uploaded in the previous reaction cycle may bind to a catalytic Mn site during the S2 → S3 transition.27,28 Density functional theory (DFT) modeling has predicted coexistence of two different conformations of the

Mn4CaO5 cluster in the S2 and S3 states, as shown by open- and closed-cubane structures in Figure 1,31,38,41,43,44,46 which could potentially cause structural flexibility of the Mn4CaO5 core. Upon the fourth oxidation by TyrZ•+, the decay of the OEC to regenerate the most reduced S0 state is believed to occur on a few millisecond time scale, with the rebinding of a substrate water molecule and the expulsion of a triplet dioxygen; however, the S3 → (S4) → S0 processes are difficult to track by currently available experimental techniques. The aim of this study is to make our initial attempt to identify possible structural reorganization during the S2 → S3 B


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Figure 3. Potential curves for interconversion between the open cubane and closed cubane structures as a function of the interatomic distance between MnD and O5 [r(MnD−O5)] in the early phase of the S2 → S3 transition; for water clusters WCYZ I/II and WCYZ III/IV, see Figure 4; S2(open)YZ•+ [H2O, HO−, H2O, −] (4443) 1{↑↓↓↑···↓} (structure A) is used as a reference for computing relative energies (ΔG); for the almost degenerate pair [1(3){↑↓↓↑···↓(↑)}, 5(7){↓↑↑↑···↓(↑)}], only the potential curve for a lower spin configuration [1{↑↓↓↑···↓}, 5{↓↑↑↑···↓}] is presented for clarity.

ensure proper positioning and orientation of mobile water molecules as well as a Cl− ion. Steric effects imposed by the protein fold were considered by fixing the atomic positions of the backbone and entire Gln165 and Asn298 residues at the periphery of the model to their X-ray structure coordinates during geometry optimizations. It should be noted that the quantum chemical description of hydrogen-bond-accepting groups from Gln165 and Asn298 are necessary to direct W4 and His190 in a proper orientation. All calculations were performed with Gaussian 0948 by using the B3LYP hybrid functional,49−51 together with the D3 version of the Grimme’s empirical dispersion with the Becke−Johnson damping function.52,53 A set of extensive basis sets was employed that consists of LANL0854 for Ca, LANL2TZ(f)54 for Mn, 6-311+G(d,p)55 for aqua/hydroxo/oxo ligands, crystallographic waters, a Cl− ion, and D95V for amino acid residues. The polarization effect by the surrounding protein environment was evaluated at each optimized geometry by the polarizable continuum model (PCM).56 The dielectric constant of 5.7 (corresponding to chlorobenzene) was used to include an implicit contribution from the low polarizability of the protein interior.

transition by means of dispersion-corrected hybrid DFT calculations. Our focus herein is on characterizing likely intermediates as a consequence of oxidation of TyrZ in the S2 state. Special attention is given to the vital role of water rearrangement near TyrZ in conducting electron and proton transfers (PTs) and substrate binding that are crucial for the catalytic chemistry of the OEC.

2. COMPUTATIONAL DETAILS As a complementary method to previous studies,45,46 we adapted herein a quantum mechanics (QM)-only approach, also called the cluster approach.47 To prepare a suitable cluster model, we started from the 1.9 Å resolution crystal structure of PSII (PDB ID: 3ARC, monomer A).8 The size of the cluster model was chosen to be sufficiently large to achieve convergence in computed relative energies of intermediates. Our model consisted of 338−341 atoms, as depicted in Figure 2, including the inorganic Mn4CaO5 cluster, 20 crystallographic waters (plus an extra water molecule), one chloride ion (Cl−), and the following amino acid residues in the first and second coordination spheres: Asp61, Tyr161 (TyrZ or YZ), Gln165, Ser169, Asp170, Asn181, Phe182 (backbone only), Val185, Glu189, His190, Asn298, Lys317, His332, Glu333, His337, Asp342, Ala344, Glu354, and Arg357. All aspartic (Asp) and glutamic (Glu) residues were assumed to be ionized, while the protonation states of histidine (His) residues were chosen to be either neutral (His190, His332) or doubly protonated (His190, His337), depending on their local environment and the redox state of TyrZ near His190. Backbone polar groups that make a hydrogen bond with waters were also treated explicitly by adding peptide units (−NH−CO−) or carbonyl groups to

3. RESULTS AND DISCUSSION As mentioned in the Introduction, the Mn4CaO5 core can exist in two different conformations called open and closed cubanes (Figure 1). Multiple charge and spin states are also possible for the OEC, with each Mn site characterized by a local high spin state SMn = 4/2 or 3/2 for an oxidation state of III (d4 configuration) or IV (d3). If water-derived terminal ligands bound to Ca and MnA (notably W1, W2, and W3) undergo C


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S2YZ•+ state, and there is no distinct structural preference between them. DFT calculations indicate that deprotonation of a terminal water ligand W1 at MnA will not occur; the protonation state [HO−, HO−, H2O, −] was found not to be an intermediate, and a proton attached to Asp61 in an initial geometry moved back to HO− (W1) to generate the neutral water in the course of the geometry optimization.57 Our calculations also suggest that deprotonation of a water ligand W3 that coordinates directly to the Ca2+ ion is strongly disfavored; PT from H2O (W3) to nearby HO− (W2) at MnA is endothermic by more than 30 kcal mol−1, as shown by diamonds in Figure 3A, even though the PT is coupled with electron shift from the resulting HO− (W3) to adjacent TyrZ•+. This means that there will be no formation of a hydroxyl radical (HO•) in the active site. Motivated by experience from our previous study using a small inorganic cluster surrounded by models of the first coordination sphere,46 we have further considered whether the hydroxo (HO−) ligand generated by W3 deprotonation might bind to a nearby vacant coordinate site at MnA of the closed cubane with concomitant stabilization. This expectation is, indeed, the case, as indicated by red triangles in Figure 3A, which show the HO−-shifted isomer [H2O, H2O, −, HO−] (structure E) to be stabilized by more than 20 kcal mol−1 than the unshifted isomer [H2O, H2O, HO•, −] in the region of the closed structure. E [H2O, H2O, −, HO−] is, however, still unstable by 4.4 kcal mol−1, as compared with B [H2O, HO−, H2O, −]. Another possibility that may cause W3 deprotonation is that ET from MnAIII to TyrZ•+ may follow the HO− (W3) shift toward MnA because the binding of the hydroxide anion is expected to raise the energy level of electrons on the coordinately saturated MnA ion. This ET was found to occur with coupled double PT from W3 to HO− (W2) and from His190−NεH+ to TyrZ−O•, leading to regeneration of the TyrZ−OH···Nε−His190 pair and accumulation of a positive charge on the Mn4 cluster (4444). This state is, hereafter, designated by S3+YZ. After the oxidation of MnAIII by TyrZ•+, the resulting closed cubane, S3(closed)+YZ [H2O, H2O, − , HO−] (4444), has a spin configuration 7{↓↑↑ ↑} with no degeneracy. Blue squares in Figure 3A provide its energy profile for the oxo migration between MnA and MnD, which indicates that the HO−-shifted state is unstable by a significant margin of about 15 kcal mol−1 with respect to B S2(closed)YZ•+ [H2O, HO−, H2O, −] (3444). These results imply that W3 deprotonation is apparently not involved in the catalytic chemistry of the OEC. We nevertheless infer after repeated trial and error that the proton-coupled electron transfer (PCET) that leads to W3 deprotonation would be thermodynamically neutral or slightly downhill under a dynamic enzyme/solvent environment. To prove this, we need to incorporate the sufficient flexibility of surrounding hydrogen-bonding environment, more specifically, different clustering structures of hydrogen-bonded water molecules near the phenolic oxygen of the TyrZ side chain. We have classified the clustering structures of hydrogen-bonded water molecules near TyrZ into four categories, WCYZ I/I′, WCYZ II, WCYZ III/III′, and WCYZ IV, according to the connectivity between TyrZ and three waters, W3, W4, and W7, as shown in Figure 4. A prime symbol (′) is used if W3 is deprotonated (W3 = HO− or HO•). In WCYZ I/I′, W4 (W3) is a hydrogen-bond donor to Gln165 and W10 (W5 and W7), and there is only one hydrogen bond between TyrZ and the water cluster, that is, between TyrZ and W7. If W4 flips its direction in WCYZ I/I′, so that W4 becomes a hydrogen-bond donor to

more than one deprotonation state, multiple protonation states of the whole cluster can also occur. To identify a state from the intricate geometric and electronic structures of the OEC, we specified the oxidation state by 3 or 4 in parentheses (MnA, MnB, MnC, MnD), the spin alignment by ↑ or ↓ in braces 2Stotal+1 {MnA, MnB, MnC, MnD···L} (L is a redox-active ligand), and the protonation states of water-derived ligands by H2O or HO− in brackets [W1, W2, W3, Win] [Win is a water-derived ligand that relocates from the W3 position to the open coordination site of the MnA ion in the closed-cubane conformation (see discussion later)]. A detailed comparison of computational and experimental spectroscopic data indicated that the protonation state of waterderived, terminal ligands in the S2 state is most likely to be [H2O, HO−, H2O, −];37 note that “−” represents “not applicable” or “not present”. We use this protonation state as a starting point for our research into the S2 → S3 transition. Absorption of a photon by PSII induces a long-range ET from redox-active Tyr161 (TyrZ) to P680•+. The rapid oxidation of TyrZ is ensured by concomitant PT from TyrZ to adjacent His190 to achieve redox leveling, thereby forming an electrically neutral tyrosine radical hydrogen-bonded to a positively charged histidine, TyrZ−O•···+HNε−His190; henceforth, this state is referred to as S2YZ•+. The structural and electronic features of S2YZ•+ are intimately related to those of the precursor S2 state because of weak magnetic interaction between the Mn4CaO5 core and TyrZ•+.39 Assuming that the oxidation state of the inorganic cluster is MnIV3MnIII in the S2YZ•+ state, the structural relaxation results in a shift of the central μ-oxo bridge (O5) toward either MnA or MnD with the IV oxidation state, forming a MnIV−O bond and leaving behind a unique five-coordinate MnD or MnA site with the III oxidation state. This bifurcation gives rise to structural and redox isomers: an open cubane with an oxidation state of (4443) and a closed cubane with an oxidation state of (3444) in Figure 1.38,46 A degenerate pair of singlet and triplet configurations, 1{↑↓↓↑ ···↓} and 3{↑↓↓↑···↑}, is favored in S2(open)YZ•+ [H2O, HO−, H2O, −] (4443), while quintet and septet configurations, 5{↓↑↑ ↑···↓} and 7{↓↑↑↑···↑}, make a degenerate pair in S2(closed)YZ•+ [H2O, HO−, H2O, −] (3444). The relative stability of the open and closed cubane structures and their interconversion in the S2 and S3 states have been the focus of much recent research.22,38,41,43,44,46 Figure 3A shows our results on potential curves for the interconversion of the open and closed cubanes as a function of interatomic distance between MnD and O5; each point was optimized with one additional fixed MnD−O5 bond. An open cubane structure A with a spin configuration of 1(3){↑↓↓↑ ···↓(↑)} in S2(open)YZ•+ and a closed cubane structure B with 5(7) {↓↑↑↑···↓(↑)} in S2(closed)YZ•+ are separated by a barrier of about 14 kcal mol−1, with the former being 1.3 kcal mol−1 more stable than the latter. The value of the barrier height, however, should be viewed with caution as DFT calculations are unable to include multiconfigurational effects that allow interchange of valence electrons residing in the MnA−O5−MnD moiety. Our result is quantitatively somewhat different from a QM(DFT + U)/MM dynamics result by Narzi et al.,44 which predicted the closed conformer to lie 2.6 kcal mol−1 below the open conformer. This small difference is not so surprising because the QM region and the methodology employed are quite different between the two studies. In the present study, the open and closed isomers are practically isoenergetic in the D


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0.6, 1.5, and 3.3 kcal mol−1 for S2(open)YZ•+ [H2O, HO−, H2O, −] (4443), S2(closed)YZ•+ [H2O, HO−, H2O, −] (3444), and S2(closed)YZ•+ [H2O, H2O, −, HO−] (3444). As a result, the energy gap between the S2YZ•+, and S3+YZ states becomes considerably small after the reorganization. The fact that S3(closed)+YZ [H2O, H2O, −, HO−] (4444) (structure F) becomes thermally accessible [5.7 kcal mol−1 above the lowest state (structure D)] deserves more than a passing notice; we will return to this point later. The above dramatic effect of water clustering near TyrZ on the energy separation between the S2YZ•+ and S3+YZ states can be analyzed by considering a PCET in eq 1, in which the left side corresponds to S2YZ•+ and the right to S3+YZ. TyrZ−O• ··· +HNε−His190 + MnA III → TyrZ−OH ··· Nε−His190 + MnA IV

total ΔG PCET

(1)

Figure 4. Classifications of clustering structures of hydrogen-bonded water molecules near Tyr161 (TyrZ).

What makes the analysis based on eq 1 complex is that the PCET reaction may be correlated not only with reorganization of the water cluster near the redox-active TyrZ but also with reorganization of the water cluster in the front of MnA, whose oxidation state changes from III to IV during the reaction. Water molecules form an extensive hydrogen-bonded network across TyrZ and MnA, and therefore, the water rearrangement near TyrZ affects preferred clustering structures near MnA to accommodate the changes in directional hydrogen-bonding interactions. We have, therefore, classified clustering structures in the front of MnA roughly into two groups, WCMnA I and WCMnA II (Figure 5), by focusing on the orientation of W5,

both TyrZ and Gln165 and an acceptor for W10, the newly formed pattern falls into the category WCYZ III/III′, in which TyrZ forms two hydrogen bonds with W4 and W7. Judging from interatomic distances, the X-ray crystal structure in the dark stable state is consistent with this pattern.8 On the other hand, if W3 on Ca2+ slightly changes its orientation in WCYZ I, two hydrogen bonds between TyrZ and W3, W7 may follow, which can be assigned to the category WCYZ II. Finally, structures featuring a maximum of three hydrogen bonds between TyrZ and the water cluster belong to the category WCYZ IV. In the present study, all patterns of the water cluster were applied to each structure in the S2YZ•+/S3+YZ state, and the complete results are shown in Tables S1 and S2. On a technical side, interconversion of I ↔ II or III ↔ IV is feasible with a slight reorientation of W3, so that the optimization of the cluster geometry tends to converge to a lower-lying structure regardless of the starting structure (but not always). In contrast, interconversion between the former (I and II) and latter (III and IV) groups is difficult or nearly impossible to achieve by a simple geometry optimization because this conversion requires simultaneous flips of three waters, W4, W10, and W20, and rearrangement of the associated hydrogenbond network. The initial geometry must be carefully chosen to incorporate sufficient structural flexibility. Figure 3A represents the result of this type of misconstruction that results in just half of the patterns, I/I′ and II, and cannot reach the rest of the half, III/III′ and IV. Figure 3B provides potential curves for the oxo transfer between MnA and MnD after the water cluster is reorganized from the groups I/I′ and II to the groups III/III′ and IV; note that the potential curves for the clusters WCYZ I and WCYZ IV are not shown in Figure 3A and B because WCYZ I and WCYZ IV are slightly unstable relative to WCYZ II and WCYZ III (Table S1). It is apparent from a comparison between Figure 3A and B that the reorganization of the water cluster has a strong influence on the energetics of the S2+YZ and S3+YZ states, as indicated by diamonds and squares in the figures. Stabilization energies as a result of conversion from I′ to III′ amount to 11.3, 11.9, and 10.5 kcal mol−1 for S2(open)+YZ [H2O, H2O, HO•, −] (4443), S2(closed)+YZ [H2O, H2O, HO•, −] (3444), and S3(closed)+YZ [H2O, H2O, −, HO−] (4444). In contrast, the water rearrangement does not significantly affect the stability of the S2YZ•+ state, with perturbed energies of only

Figure 5. Classifications of clustering structures of hydrogen-bonded water molecules near MnA.

although there are many variants within the same group (e.g., W3, if present, may have a hydrogen bond with W6 or Win). In WCMnA I, W5 is hydrogen-bonded to W6 and Win, while in WCMnA II, W5 is flipped to form hydrogen bonds with W6 and the backbone carbonyl group of Asp170, instead of Win. Competition between two available conformations allows the water cluster to undergo WCMnA I ↔ WCMnA II conversion, E


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Figure 6. (A) Energy diagrams for the PCET reaction in the less hydrated state that converts S2(closed)YZ•+ [H2O, H2O, −, HO−] (3444) 5(7){↓↑↑↑ ···↓(↑)} (colored red) into S3(closed)+YZ [H2O, H2O, −, HO−] (4444) 7{↓↑↑↑} (colored blue); for water clusters WCYZ I′ and WCYZ III′, see Figure 4; for water clusters WCMnA I and WCMnA II, see Figure 5; S2(open)YZ•+ [H2O, HO−, H2O, −] (4443) 1{↑↓↓↑···↓} (structure A) is used as a reference for computing relative energies in kcal mol−1. (B) Energy diagrams for the PCET reaction in the more hydrated state that converts S2(closed)WYZ•+ [H2O, H2O, H2O, HO−] (3444) 5(7){↓↑↑↑···↓(↑)} (colored red) into S3(closed)W+YZ [H2O, H2O, H2O, HO−] (4444) 7{↓↑↑↑} (colored blue); for water clusters WCYZ I/II and WCYZ III/IV, see Figure 4; for water clusters WCMnA I and WCMnA II, see Figure 5; S2(closed)WYZ•+ [H2O, H2O, H2O, HO−] (3444) 5{↓↑↑↑···↓} (structure EW) is used as a reference for computing relative energies in kcal mol−1.

which enables facile inner-sphere proton relocation between W2 and Win via a water bridge W5 in WCMnA I. By discriminating between WCMnA I and WCMnA II, the overall PCET energy ΔGtotal PCET can be separated into two terms, as indicated in eq 2, in which one is related to a PCET reaction without reorganization of the water cluster near MnA (ΔGPCET) and the other is associated with a single flip of W5, that is, WCMnA I ↔ WCMnA II interconversion (ΔGr). total ΔG PECT

= ΔG PCET + ΔGr

TyrZ−O• ··· +HNε−His190 + MnA III → TyrZ−O− ··· +HNε−His190 + MnA IV

ΔG ET (3)

TyrZ−O− ··· +HNε−His190 + MnA IV → TyrZ−OH ··· Nε−His190 + MnA IV

ΔG PT

(4)

We have applied the above energy decomposition scheme (ΔGtotal PCET = ΔGET + ΔGPT + ΔGr) to the PCET reaction that converts S2(closed)YZ•+ [H2O, H2O, −, HO−] (3444) 5(7){↓↑↑ ↑···↓(↑)} into S3(closed)+YZ [H2O, H2O, −, HO−] (4444) 7{↓ ↑↑↑}, in such a way that a single flip of W5 occurs before the PCET reaction in eqs 3 and 4 (i.e., ΔGr is assumed to be an energy required to preorganize flexible W5 prior to the PCET reaction), as depicted in Figure 6A.59

(2)

The PCET process without reorganization of the water cluster near MnA can be further decomposed into a two-step sequence involving an initial ET followed by a subsequent PT, as shown in eqs 3 and 4, in which ΔGPCET = ΔGET + ΔGPT.58 F


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could be the origin of the positive sign of ΔΔGPT. In contrast, the ΔΔGET value for ET is very large and negative (−8.8 kcal mol−1), which dominates the overall PCET energy (ΔΔGtotal PCET = −7.0 kcal mol−1). This is a role played by the water cluster near TyrZ, notably dynamic W4, W10, and W20, through their electrostatic influence on the redox potential of the TyrZ−O•/ TyrZ−O− couple. On the other hand, the preorganization of the water cluster near MnA makes a negligible contribution (ΔΔGr = −0.1 kcal mol−1) to the overall PCET energy due to small values of ΔGr (less than 2 kcal mol−1) and cancellation between WCYZ I′ and WCYZ III′. Figure 7 summarizes our proposed mechanism in the early phase of the S2 → S3 transition; structures A−F correspond to the ones in Figure 3. In the S2(open)YZ•+ state, there are closely lying different clustering structures of water near TyrZ•+, WCYZ II (A) and WCYZ III (C), that can interconvert reversibly by a flip of W4 followed by reorientations of W10 and W20 as well as dissociation of W3; the energy gap between A and C is only 0.61 kcal mol−1 (Table S1). The rapid equilibrium, WCYZ II (A) ↔ WCYZ III (C), confers a high degree of flexibility and mobility on the water cluster, which is maintained even when the oxo ligand (O5) transfers from MnD to MnA because closely lying structures are also available in the S2(closed)YZ•+ state (Table S1): WCYZ I (not shown in Figure 7) ↔ WCYZ II (B) ↔ WCYZ III (D) ↔ WCYZ IV (not shown). The importance of a swinging motion of W3 caused by the multiple populations of them cannot be overemphasized. W3 is trapped on the phenolic oxygen of TyrZ•+ in WCYZ II but is released and slightly shifted toward MnA in WCYZ III because of loss of a hydrogen bond with TyrZ•+, as illustrated in Figure 7. The interatomic distance between the oxygen atom of W3 and MnA indeed decreases from 4.287 (A) to 4.029 Å (C) in S2(open)YZ•+ and from 4.247 (B) to 3.800 Å (D) in S2(closed)YZ•+, showing a large fluctuation of W3. It is in the closed cubane structure that the increased mobility of W3 has a very important implication because there is a large free space just below W3 in this conformation, as indicated by a dashed circle in D in Figure 7. W3 can effectively occupy this large space and coordinate to a vacant MnA site, if the movement of W3 is coupled with deprotonation of W3, which is also possible in the closed cubane structure because of the presence of a neighboring proton acceptor HO− (W2), colored dark green in Figure 7, and a PT mediator (W5) between W3 and HO− (W2). The larger mobility of W3 is consistent with the results of structural analysis of Sr2+-substituted PSII, where the position of W3 was found to be largely affected relative to other water ligands.61 We envision that a vacant W3 position left on Ca2+ in F will be filled with W4 followed by sequential migrations of W10 and W20 that are connected to one of the putative channels for water transport.8,9,62 A similar mechanism was suggested by Bovi et al., albeit for the S2 state.41 It was estimated from a recent steered molecular dynamics simulation that water can permeate through this channel with a low activation energy (∼10 kcal mol−1).63 Unfortunately, the present cluster model is unable to evaluate a free-energy change associated with water permeation through the channel. Alternatively, we may evaluate energy levels of the quadruply water-shifted structure (W3 → Win, W4 → W3, W10 → W4, W20 → W10) as a transient stage leading to water entry, as illustrated in Figure 8. Figure 8A shows potential curves for quadruply water-shifted structures in the S2(closed)YZ•+ state with WCYZ II and WCYZ III and in the S3(closed)+YZ state with WCYZ III. The water relocation

Table 1 provides computed ΔGtotal PCET, ΔGPCET, ΔGET, ΔGPT, and ΔGr values separately for each water cluster surrounding Table 1. Energy Decomposition Analysis of the PCET Reaction That Converts S2(closed)YZ•+ [H2O, H2O, −, HO−] (3444) 5(7){↓↑↑↑···↓(↑)} into S3(closed)+YZ [H2O, H2O, −, HO−] (4444) 7{↓↑↑↑}a ΔGPCET WCYZ I′ WCYZ III′ ΔΔGb

ΔGtotal PCET

ΔGET

ΔGPT

ΔGr

+10.3 +3.3 −7.0

+11.3 +2.5 −8.8

−2.8 −0.9 +1.9

+1.8 +1.7 −0.1

For definitions of ΔGtotal PCET, ΔGPCET, ΔGET, ΔGPT, and ΔGr, see Figure 6A and eqs 1−4; for water clusters WCYZ I′ and WCYZ III′, see Figure 4; Nε···H bond distances of TyrZ−O−···+HNε−His190 were fixed at the corresponding values of TyrZ−O•···+HNε−His190 (1.046 and 1.036 Å for WCYZ I′ and WCYZ III′) during geometry optimizations; relative energies are given in kcal mol−1. bΔΔG ≡ ΔG(WCYZ III′) − ΔG(WCYZ I′). a

TyrZ (WCYZ I′/WCYZ III′). Also shown is the difference in the reaction energy between WCYZ I′ and WCYZ III′ [ΔΔG ≡ ΔG(WCYZ III′) − ΔG(WCYZ I′)], which can be used in an approximate manner to identify the thermodynamic origin of the remarkable effect of the water cluster near TyrZ on the energetics of the S2YZ•+ and S3+YZ states because the effects of reorganizations of surrounding environment other than that associated with water relocation near TyrZ are effectively canceled out. A negative sign of ΔΔG means that the reorganization of the water cluster from WCYZ I′ to WCYZ III′ provides a favorable electrostatic environment for the corresponding reaction. The calculated ΔΔGPT value for PT is relatively small and positive (+1.9 kcal mol−1). This is compatible with a QM/MM study by Saito et al., which clarified that the water cluster near TyrZ, especially W7, plays a role in shortening a distance between TyrZ and His190.60 In the present study, W7 is tightly bound to both TyrZ and Glu189 throughout the reaction, thereby leading to modulation of the pKa value of TyrZ60 and the stability of ΔGPT. The formation of a hydrogen bond between TyrZ and W4 is also expected to lower, to a certain degree, the pKa value of TyrZ, as can be seen in a longer TyrZ−O−···H+ distance (1.366 Å) and a shorter H+···Nε−His190 distance (1.135 Å) for WCYZ III′ than those for WCYZ I′ (1.064 and 1.366 Å), as shown in Table 2, even though the reduction of TyrZ•+ raises its pKa value substantially [compare between S2(closed)YZ•+ and S3(closed)+YZ]. Competition between attractive and repulsive effects in WCYZ III′ Table 2. Interatomic Distances of the TyrZ−O···H+···Nε− His190 Moiety for S2(closed)YZ•+ [H2O, H2O, −, HO−] (3444) 5(7){↓↑↑↑···↓(↑)} and S3(closed)+YZ [H2O, H2O, −, HO−] (4444) 7{↓↑↑↑}a WCYZ I′

S2(closed)YZ•+ S3(closed)+YZ

WCYZ III′

r(TyrZ− O···H+)b

r(H ···Nε− His190)b


r(H+···Nε− His190)b

1.690 1.064

1.047 1.501

1.690 1.366

1.047 1.135

+

a

For water clusters WCYZ I′ and WCYZ III′, see Figure 4. bInteratomic distances between the oxygen atom of TyrZ and a proton [r(TyrZ−O··· H+)] and between the Nε atom of His190 and a proton [r(H+···Nε− His190)] are given in Å. G


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Figure 7. Mechanism of the early phase of the S2 → S3 transition; for water clusters WCYZ I/II and WCYZ III/IV, see Figure 4; two substrate oxygens are colored cyan; a base that abstracts a proton from a substrate water molecule is colored dark green; a hydrogen bond that has a strong influence on the redox potential of the TyrZ−O•/TyrZ−O− couple is colored light green; dashed circles represent internal cavities responsible for W3 → Win water relocation that may lead to hydration of the catalytic site.

in Figure 8, can be further filled with one additional water molecule, which likely becomes a substrate in the next or later cycle. Such hydrated states are, henceforth, specified by adding a subscript W: S2(closed)WYZ•+ [H2O, H2O, H2O, HO−] (3444) 5(7){↓↑↑↑···↓(↑)} and S3(closed)W+YZ [H2O, H2O, H2O, HO−] (4444) 7{↓↑↑↑}. Much like the case with the S2(closed)YZ•+ and S3(closed)+YZ states, the relative stability of the S2(closed)WYZ•+ and S3(closed)W+YZ states is also strongly influenced by the water cluster near TyrZ, as shown in Figure 6B, which demonstrates that the water rearrangement WCYZ I/ II → WCYZ III/IV stabilizes S3(closed)W+YZ [H2O, H2O, H2O, HO−] (4444) 7{↓↑↑↑} (colored blue in Figure 6B) much more than S2(closed)WYZ•+ [H2O, H2O, H2O, HO−] (3444) 5(7){↓↑↑ ↑···↓(↑)} (colored red). Table 3 summarizes an analysis of dominant contributions to thermodynamics for the PCET reaction in the more hydrated state. The major stabilization energy of S3(closed)W+YZ relative to S2(closed)WYZ•+ as a result total of the water relocation near TyrZ [ΔΔGtotal PCET = ΔGPCET(WCYZ −1 total III/IV) − ΔGPCET(WCYZ I/II) = −7.4 kcal mol ] comes from a significant change in energy released when an electron on MnAIII is transferred to TyrZ−O• to form TyrZ−O− (ΔΔGET = −9.8 kcal mol−1), while the effects of pKa shifting (ΔΔGPT = +0.4 kcal mol−1) and preorganization of the clustering structure near MnA (ΔΔGr = +2.0 kcal mol−1) are minor factors. Again, the degree of PT from Nε−His190 to TyrZ−O− in the S3(closed)W+YZ state depends significantly on the clustering structure near TyrZ, as shown in Table 4; TyrZ−O−···H+ and

stabilizes significantly the S3(closed)+YZ state with WCYZ III (structure F′) that originates from F as well as the S2(closed)YZ•+ state with WCYZ II (structure E′) that stems from E. E′ and F′ are thermally accessible; E′ lies only 0.7 kcal mol−1 above B, and F′ is 1.7 kcal mol−1 above D. It is known that the energy change associated with oxidation/ reduction of the Mn site depends strongly on the amount of the Hartree−Fock (HF) exchange and that the B3LYP* functional with reduced HF exchange from standard 20 to 15% is more suitable for transition-metal complexes.64,65 The potential curves by B3LYP* are given in Figure 8B; note that all relative energies were computed using B3LYP-D3 (HF 20%) optimized geometries and include B3LYP (HF 20%) dispersion corrections because the D3 parameters are not defined for B3LYP* (HF 15%). Downsizing the HF weight substantially lowers the oxidized state (4444) with respect to the reduced states (3444)/(4443); E (3444), E′ (3444), F (4444), and F′ (4444) are calculated to be 5.8 (6.0), 2.0 (1.8), 5.7 (0.6), and 1.5 (−4.0) kcal mol−1 above A (4443) at the B3LYP (B3LYP*) level. The S3(closed)+YZ state with WCYZ III (F′) becomes virtually the lowest-lying intermediate at the B3LYP* level. The optimal empirical parameters of the hybrid DFT method are, however, unknown for the present system, and therefore, there is a clear need for development of theoretical methods to handle electron correlation more accurately. An empty space (W20 position) left in the periphery of the quadruply water-shifted model, as indicated by a dashed circle H


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Figure 8. Potential curves for quadruply water-shifted structures as a function of interatomic distance between MnD and O5 [r(MnD−O5)] in the early phase of the S2 → S3 transition by B3LYP (HF 20%) (A) and B3LYP* (HF 15%) (B); B3LYP* energies were computed using B3LYP-D3optimized geometries and include B3LYP dispersion corrections; for water clusters WCYZ II and WCYZ III, see Figure 4; S2(open)YZ•+ [H2O, HO−, H2O, −] (4443) 1{↑↓↓↑···↓} (structure A) is used as a reference for computing relative energies (ΔG); for the almost degenerate pair 5(7){↓↑↑↑ ···↓(↑)}, only the potential curve for a lower spin configuration 5{↓↑↑↑···↓} is presented for clarity; a dashed circle represents a vacant position as a result of quadruple water shift (W3 → Win, W4 → W3, W10 → W4, W20 → W10).

H+···Nε−His190 distances in WCYZ III/IV are unusually long (1.482 Å) and short (1.100 Å), as compared with those in WCYZ I/II (1.281 and 1.209 Å), in accordance with the positive sign of ΔΔGPT. One important point that can be seen from a comparison between the less hydrated state (Figure 6A) and the more hydrated state (Figure 6B) is that the hydration of the catalytic site, that is, the saturation of coordination sites in the Mn4CaO5 cluster, gives rise to electrostatic changes that are substantially more favorable in S3+YZ than in S2YZ•+, as evidenced by ΔGtotal PCET values that are markedly decreased from +10.3 to +4.8 kcal mol−1 for WCYZ I/I′ and II and from +3.3 to −2.6 kcal mol−1 for WCYZ III/III′ and IV. Importantly, the cluster reorganization WCYZ I/II → WCYZ III/IV causes the S3(closed)W+YZ state to lie below the S2(closed)WYZ•+ state if the catalytic site is more solvated, thereby yielding S3(closed)W+YZ [H2O, H2O, H2O, HO−] (4444) 7{↓↑↑↑} (structure FW in Figures 6B and 7), which is located 3.6 (7.4) kcal mol−1 below S2(closed)WYZ•+ [H2O, H2O, H2O, HO−] (3444) 5(7){↓↑↑↑···↓(↑)} (structure EW favored in WCYZ I/II) at the B3LYP (B3LYP*) level. This exothermicity serves as a thermodynamic driving force for the PCET reaction that converts S2(closed)WYZ•+ into S3(closed)W+YZ under dynamic enzyme/solvent environment. These results mean that the early phase of the S2 → S3 transition may be described as an ensemble of S 2 (open/closed)Y Z • + , S 3 (closed) + Y Z , S2(closed)WYZ•+, and S3(closed)W+YZ and that ET from MnAIII to TyrZ•+ could be induced thermally by large reorganization of water molecules surrounding TyrZ and/or hydration of the Mn4CaO5 cluster.

Table 3. Energy Decomposition Analysis of the PCET Reaction That Converts S2(closed)WYZ•+ [H2O, H2O, H2O, HO−] (3444) 5(7){↓↑↑↑···↓(↑)} into S3(closed)W+YZ [H2O, H2O, H2O, HO−] (4444) 7{↓↑↑↑}a ΔGPCET WCYZ I/II WCYZ III/IV ΔΔGb

ΔGtotal PCET

ΔGET

ΔGPT

ΔGr

+4.8 −2.6 −7.4

+5.3 −4.5 −9.8

−0.8 −0.4 +0.4

+0.3 +2.3 +2.0

For definitions of ΔGtotal PCET, ΔGPCET, ΔGET, ΔGPT, and ΔGr, see Figure 6B and eqs 1−4; for water clusters WCYZ I/II and WCYZ III/ IV, see Figure 4; Nε···H bond distances of TyrZ−O−···+HNε−His190 were fixed at the corresponding values of TyrZ−O•···+HNε−His190 (1.039 and 1.034 Å for WCYZ I/II and WCYZ III/IV) during geometry optimizations; relative energies are given in kcal mol−1. bΔΔG ≡ ΔG(WCYZ III/IV) − ΔG(WCYZ I/II). a

Table 4. Interatomic Distances of the TyrZ−O···H+···Nε− His190 Moiety for S2(closed)WYZ•+ [H2O, H2O, H2O, HO−] (3444) 5(7){↓↑↑↑···↓(↑)} and S3(closed)W+YZ [H2O, H2O, H2O, HO−] (4444) 7{↓↑↑↑}a WCYZ I/II

S2(closed)WYZ•+ S3(closed)W+YZ

WCYZ III/IV


r(H ···Nε− His190)b


r(H+···Nε− His190)b

1.720 1.281

1.039 1.209

1.626 1.482

1.040 1.100

+

a

For water clusters WCYZ I/II and WCYZ III/IV, see Figure 4. Interatomic distances between the oxygen atom of TyrZ and a proton [r(TyrZ−O···H+)] and between the Nε atom of His190 and a proton [r(H+···Nε−His190)] are given in Å. b

I


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(5) Shen, J.-R. The Structure of Photosystem II and the Mechanism of Water Oxidation in Photosynthesis. Annu. Rev. Plant Biol. 2015, 66, 23−48. (6) Ferreira, K. N.; Iverson, T. M.; Maghlaoui, K.; Barber, J.; Iwata, S. Architecture of the Photosynthetic Oxygen-Evolving Center. Science 2004, 303, 1831−1838. (7) Loll, B.; Kern, J.; Saenger, W.; Zouni, A.; Biesiadka, J. Toward Complete Cofactor Arrangement in the 3.0 Å Resolution Structure of Photosystem II. Nature 2005, 438, 1040−1044. (8) Umena, Y.; Kawakami, K.; Shen, J.-R.; Kamiya, N. Crystal Structure of Oxygen-Evolving Photosystem II at a Resolution of 1.9 Å. Nature 2011, 473, 55−60. (9) Kawakami, K.; Umena, Y.; Kamiya, N.; Shen, J.-R. Structure of the Catalytic, Inorganic Core of Oxygen-Evolving Photosystem II at 1.9 Å Resolution. J. Photochem. Photobiol., B 2011, 104, 9−18. (10) Suga, M.; Akita, F.; Hirata, K.; Ueno, G.; Murakami, H.; Nakajima, Y.; Shimizu, T.; Yamashita, K.; Yamamoto, M.; Ago, H.; Shen, J.-R. Native Structure of Photosystem II at 1.95 Å Resolution Viewed by Femtosecond X-ray Pulses. Nature 2015, 517, 99−103. (11) 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. (12) Styring, S.; Rutherford, A. W. The Microwave Power Saturation of SIIslow Varies with the Redox State of the Oxygen-Evolving Complex in Photosystem II. Biochemistry 1988, 27, 4915−4923. (13) Roelofs, T. A.; Liang, W.; Latimer, M. J.; Cinco, R. M.; Rompel, A.; Andrews, J. C.; Sauer, K.; Yachandra, V. K.; Klein, M. P. Oxidation States of the Manganese Cluster during the Flash-Induced S-State Cycle of the Photosynthetic Oxygen-Evolving Complex. Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 3335−3340. (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) Messinger, J.; Robblee, J. H.; Bergmann, U.; Fernandez, C.; Glatzel, P.; Visser, H.; Cinco, R. M.; McFarlane, K. L.; Bellacchio, E.; Pizarro, S. A.; et al. Absence of Mn-Centered Oxidation in the S2 → S3 Transition: Implications for the Mechanism of Photosynthetic Water Oxidation. J. Am. Chem. Soc. 2001, 123, 7804−7820. (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) Liang, W.; Roelofs, T. A.; Cinco, R. M.; Rompel, A.; Latimer, M. J.; Yu, W. O.; Sauer, K.; Klein, M. P.; Yachandra, V. K. Structural Change of the Mn Cluster during the S2 → S3 State Transition of the Oxygen-Evolving Complex of Photosystem II. Does It Reflect the Onset of Water/Substrate Oxidation? Determination by Mn X-ray Absorption Spectroscopy. J. Am. Chem. Soc. 2000, 122, 3399−3412. (18) Robblee, J. H.; Messinger, J.; Cinco, R. M.; McFarlane, K. L.; Fernandez, C.; Pizarro, S. A.; Sauer, K.; Yachandra, V. K. The Mn Cluster in the S0 State of the Oxygen-Evolving Complex of Photosystem II Studied by EXAFS Spectroscopy: Are There Three Di-μ-oxo-bridged Mn2 Moieties in the Tetranuclear Mn Complex? J. Am. Chem. Soc. 2002, 124, 7459−7471. (19) Glöckner, C.; Kern, J.; Broser, M.; Zouni, A.; Yachandra, V.; Yano, J. Structural Changes of the Oxygen-Evolving Complex in Photosystem II during the Catalytic Cycle. J. Biol. Chem. 2013, 288, 22607−22620. (20) Karge, M.; Irrgang, K.-D.; Renger, G. Analysis of the Reaction Coordinate of Photosynthetic Water Oxidation by Kinetic Measurements of 355 nm Absorption Charges at Different Temperatures in Photosystem II Preparations Suspended in Either H2O or D2O. Biochemistry 1997, 36, 8904−8913.

4. CONCLUSIONS The present hybrid DFT study investigated the early phase of S2 → S3 transition in the OEC of PSII and revealed that oxidation of the Mn4CaO5 core by TyrZ•+ occurs through a sequence of events involving open → closed interconversion followed by movement of W3 toward the MnA site (substrate binding) with a coupled W3 → HO− (W2) proton shift (substrate deprotonation). The rearrangement of the hydrogenbond pattern near TyrZ has a very large impact on the relative stability of the S2YZ•+ and S3+YZ states, demonstrating a strong coupling between water dynamics and ET from MnAIII to TyrZ•+. The hydration of the catalytic site, which may be induced by the W3 migration, acts synergistically with the water rearrangement near TyrZ to drive the oxidation reaction, S2YZ•+ → S3+YZ. It is the directed electrostatic property of the water cluster under the specific local protein environment that leads to its special ability to influence catalytic progression by strengthening hydrogen-bonding interactions with active-site residues and the Mn4CaO5 cofactor. These findings highlight the important biological role of water molecules in the vicinity of the Mn4CaO5 core; they do not just contribute to structural stability and flexibility but participate actively in the catalysis by mediating short-range proton relocation and providing an appropriate electrostatic environment for critical redox processes. Important mechanistic consequences of the substrate binding and active-site hydration during S2 → S3 transition will be discussed elsewhere.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.5b05740. Energy decomposition analyses of PCET reactions and relative energies, interatomic distances, Mulliken charge and spin densities, Cartesian coordinates, absolute energies, and ⟨S2⟩ values of key intermediates (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] or [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by a Grant-in-Aid for Specially Promoted Research (No. 24000018) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Computations were carried out using the Research Center for Computational Science, Okazaki, Japan.

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REFERENCES

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