Diastereoselective Hydroxylation of N-tert-Butanesulfinyl Imines with 2-(Phenylsulfonyl)-3-phenyloxaziridine (Davis Oxaziridine).

The diastereoselective α-hydroxylation of N-tert-butanesulfinyl metallodienenamine and metalloenamines with Davis oxaziridine affords α-hydroxy N-sulfinyl imines with 50-88% yield and up to 98:2 diastereomeric ratio. Dramatic changes in diastereoselectivity and stereoselectivity were observed by choice of metal bases. The mechanistic understanding for the switch in diastereoselectivity was assisted by DFT computational modeling, which suggests the facial approach is governed by aza-enolate geometry. A one-pot protocol for the asymmetric synthesis of 1,2-amino alcohols is described.

Intramolecular Natural Energy Decomposition Analysis: Applications to the Rational Design of Foldamers.

We describe an intramolecular version of the natural energy decomposition analysis (NEDA), with the aim of evaluating interactions between molecular fragments across covalent bonds. The electronic energy in intramolecular natural energy decomposition analysis (INEDA) is divided into electrical, core, and charge transfer components. The INEDA method describes the fragments using the nonfragmented electronic density, and, therefore, there are no limitations in how to choose the boundary orbital. We used INEDA to evaluate the interaction energies that give origin to barriers of rotation around Camide Caromatic (Cam Car ) and Namide Caromtaic (Nam Car ) bonds in arylamide-foldamer building blocks. We found that differences of barrier height between models with different ortho-aryl substituents stem from charge transfer and core interactions. In three-center hydrogen-bond (H-bond) models with an NH proton donor H-bound to two electronegative ortho-aryl substituents, the interaction energy of the three-center system is larger than in either of the two-center H-bond subsystem alone, indicating an increase of overall rigidity. The combination of INEDA and NEDA allows the evaluation of intermolecular and intramolecular interactions using a consistent theoretical framework. © 2018 Wiley Periodicals, Inc.

A DFT/B3LYP study of the mechanisms of the O2 formation reaction catalyzed by the [(terpy)(H2O)MnIII(O)2MnIV(OH2)(terpy)](NO3)3 complex: A paradigm for photosystem II.

We present a theoretical study of the reaction pathway for dioxygen molecular formation catalyzed by the [(terpy)(H2O)MnIII(O)2MnIV(OH2) (terpy)](NO3)3 (terpy=2,2':6',2″-terpyridine) complex based on DFT-B3LYP calculations. In the initial state of the reaction, a partial oxido radical (0.44 spins) is formed ligated to Mn. This radical is involved in a nucleophylic attack by bulk water in the OO bond reaction formation step, in which the oxido fractional unpaired electron is delocalized toward the outermost Mn of the µ-oxo bridge, instead of the ligated Mn center. The reaction then follows with a series of proton-coupled electron transfer steps, in which the oxidation state, as well as the bond strength of the OO moiety increase, while the OOMn(1) bond gets weaker until O2 is released. In this model, basic acetate ions from the buffer solution capture protons in the proton-transfer steps. In each step there is reduction of the OOMn(1) binding strength, with concomitant increase of the OO bond strength, which culminates with the release of O2 in the last step. This last step is entropy driven, while formation of hydroperoxide and superoxide moieties is enthalpy driven. According with experiments, the rate-limiting step is the double oxidation of Mn(IV,III) or peroxymonosulfate binding, which occur prior to the OO bond formation step. This supports our findings that the barriers of all intermediate steps are below the experimental barrier of 19-21kcal/mol. The implications of these findings for understanding photosynthetic water-splitting catalysis are also discussed.

Geometrical properties of the manganese(iv)/iron(iii) cofactor of Chlamydia trachomatis ribonucleotide reductase unveiled by simulations of XAS spectra.

Using simulations of Mn/Fe K-edge X-ray absorption spectroscopy (XAS), combined with DFT-optimized structural models and direct comparisons with available experimental data, we determine geometrical and electronic properties of the Mn-Fe active site of Chlamydia trachomatis (Ct) of ribonucleotide reductase (RNR). In the post-edge XAS energy range, we use extended X-ray absorption fine structure (EXAFS) data, to acquire absorber-scatterer geometrical information around each absorber metal center. For this task, we apply a protocol that evaluates Debye-Waller factors in scattering paths instead of scattering shells to fit the experimental EXAFS. The model of the manganese(iv)/iron(iii) cofactor that best fit Mn and Fe K-edge EXAFS experimental data is a structure with Mn at metal site 1 (proximal to Phe-127), a µ-oxo/µ-hydroxo/µ-1,3-carboxylato core, and a terminal hydroxo ligand, i.e. OH--Mn1(iv)-(µ-O)(µ-OH-)-Fe2(iii).

Opsin Effect on the Electronic Structure of the Retinylidene Chromophore in Rhodopsin.

Direct examination of experimental NMR parameters combined with electronic structure analysis was used to provide a first-principle interpretation of NMR experiments and give a precise evaluation of how the electronic perturbation of the protein environment affects the electronic properties of the retinylidene chromophere in rhodopsin. To this end, we pursued a theoretical analysis using a combination of tools including quantum mechanics/molecular mechanics (QM/MM) at the Density Functional Theory (DFT) level, in conjunction with gauge independent atomic orbital (GIAO) calculations of (13)C NMR chemical shieldings and (1)J(CC) spin-spin coupling constants obtained with the Coupled Perturbed DFT (CPDFT) method. The opsin effect on the retinylidene chromophere is interpreted as an inductive effect of Glu-113 which readjusts the weighting factors of resonance substructures of the conjugated chain of the chromophere. These changes give a rationalization to the alternating effect of the (13)C chemical shifts magnitudes when comparing the retinylidene chromophere in the presence and absence of the protein environment. Conversely, perturbation of π orbitals has little to no effect over (1)J (13)C-(13)C spin-spin coupling constants, as they are mainly dominated by the Fermi contact term, and hence the counteraion effect is restricted to the vicinity of the perturbation. Thus, the apparent contradiction between experimental findings based on chemical shifts (deep penetration) and one-bond J-couplings (localized effects of the protonated Schiff base at the chain terminus) is in fact a consequence of different properties responding differently to the same external perturbation.

Reversible visible-light photooxidation of an oxomanganese water-oxidation catalyst covalently anchored to TiO2 nanoparticles.

Several polynuclear transition-metal complexes, including our own dinuclear di-µ-oxo manganese compound [H(2)O(terpy)Mn(III)(µ-O)(2)Mn(IV)(terpy)H(2)O](NO(3))(3) (1, terpy = 2,2':6',2''-terpyridine), have been reported to be homogeneous catalysts for water oxidation. This paper reports the covalent attachment of 1 onto nanoparticulate TiO(2) surfaces using a robust chromophoric linker L. L, a phenylterpy ligand attached to a 3-phenyl-acetylacetonate anchoring moiety via an amide bond, absorbs visible light and leads to photoinduced interfacial electron transfer into the TiO(2) conduction band. We characterize the electronic and structural properties of the 1-L-TiO(2) assemblies by using a combination of methods, including computational modeling and UV-visible, IR, and EPR spectroscopies. We show that the Mn(III,IV) state of 1 can be reversibly advanced to the Mn(IV,IV) state by visible-light photoexcitation of 1-L-TiO(2) nanoparticles (NPs) and recombines back to the Mn(III,IV) state in the dark, in the absence of electron scavengers. Our findings also indicate that a high degree of crystallinity of the TiO(2) NPs is essential for promoting photooxidation of the adsorbates by photoinduced charge separation when the TiO(2) NPs serve as electron acceptors in artificial photosynthetic assemblies. The reported results are particularly relevant to the development of photocatalytic devices for oxidation chemistry based on inexpensive materials (e.g., TiO(2) and Mn complexes) that are robust under aqueous and oxidative conditions.

The MoD-QM/MM methodology for structural refinement of photosystem II and other biological macromolecules.

Quantum mechanics/molecular mechanics (QM/MM) hybrid methods are currently the most powerful computational tools for studies of structure/function relations and structural refinement of macrobiomolecules (e.g., proteins and nucleic acids). These methods are highly efficient, since they implement quantum chemistry techniques for modeling only the small part of the system (QM layer) that undergoes chemical modifications, charge transfer, etc., under the influence of the surrounding environment. The rest of the system (MM layer) is described in terms of molecular mechanics force fields, assuming that its influence on the QM layer can be roughly decomposed in terms of electrostatic interactions and steric hindrance. Common limitations of QM/MM methods include inaccuracies in the MM force fields, when polarization effects are not explicitly considered, and the approximate treatment of electrostatic interactions at the boundaries between QM and MM layers. This article reviews recent advances in the development of computational protocols that allow for rigorous modeling of electrostatic interactions in extended systems beyond the common limitations of QM/MM hybrid methods. We focus on the moving-domain QM/MM (MoD-QM/MM) methodology that partitions the system into many molecular domains and obtains the electrostatic and structural properties of the whole system from an iterative self-consistent treatment of the constituent molecular fragments. We illustrate the MoD-QM/MM method as applied to the description of photosystem II as well as in conjunction with the application of spectroscopically constrained QM/MM optimization methods, based on high-resolution spectroscopic data (extended X-ray absorption fine structure spectra, and exchange coupling constants).

Computational insights into the O2-evolving complex of photosystem II.

Mechanistic investigations of the water-splitting reaction of the oxygen-evolving complex (OEC) of photosystem II (PSII) are fundamentally informed by structural studies. Many physical techniques have provided important insights into the OEC structure and function, including X-ray diffraction (XRD) and extended X-ray absorption fine structure (EXAFS) spectroscopy as well as mass spectrometry (MS), electron paramagnetic resonance (EPR) spectroscopy, and Fourier transform infrared spectroscopy applied in conjunction with mutagenesis studies. However, experimental studies have yet to yield consensus as to the exact configuration of the catalytic metal cluster and its ligation scheme. Computational modeling studies, including density functional (DFT) theory combined with quantum mechanics/molecular mechanics (QM/MM) hybrid methods for explicitly including the influence of the surrounding protein, have proposed chemically satisfactory models of the fully ligated OEC within PSII that are maximally consistent with experimental results. The inorganic core of these models is similar to the crystallographic model upon which they were based, but comprises important modifications due to structural refinement, hydration, and proteinaceous ligation which improve agreement with a wide range of experimental data. The computational models are useful for rationalizing spectroscopic and crystallographic results and for building a complete structure-based mechanism of water-splitting in PSII as described by the intermediate oxidation states of the OEC. This review summarizes these recent advances in QM/MM modeling of PSII within the context of recent experimental studies.

A model of the oxygen-evolving center of photosystem II predicted by structural refinement based on EXAFS simulations.

A refined computational structural model of the oxygen-evolving complex (OEC) of photosystem II (PSII) is introduced. The model shows that the cuboidal core Mn3CaO4 with a "dangler" Mn ligated to a corner mu4-oxide ion is maximally consistent with the positioning of the amino acids around the metal cluster as characterized by XRD models and high-resolution spectroscopic data, including polarized EXAFS of oriented single crystals and isotropic EXAFS. It is, therefore, natural to expect that the proposed structural model should be particularly useful to establish the structure of the OEC, consistently with high-resolution spectroscopic data, and for elucidating the mechanism of water-splitting in PSII as described by the intermediate oxidation states of the EC along the catalytic cycle.

Quantum mechanics/molecular mechanics study of the catalytic cycle of water splitting in photosystem II.

This paper investigates the mechanism of water splitting in photosystem II (PSII) as described by chemically sensible models of the oxygen-evolving complex (OEC) in the S0-S4 states. The reaction is the paradigm for engineering direct solar fuel production systems since it is driven by solar light and the catalyst involves inexpensive and abundant metals (calcium and manganese). Molecular models of the OEC Mn3CaO4Mn catalytic cluster are constructed by explicitly considering the perturbational influence of the surrounding protein environment according to state-of-the-art quantum mechanics/molecular mechanics (QM/MM) hybrid methods, in conjunction with the X-ray diffraction (XRD) structure of PSII from the cyanobacterium Thermosynechococcus elongatus. The resulting models are validated through direct comparisons with high-resolution extended X-ray absorption fine structure spectroscopic data. Structures of the S3, S4, and S0 states include an additional mu-oxo bridge between Mn(3) and Mn(4), not present in XRD structures, found to be essential for the deprotonation of substrate water molecules. The structures of reaction intermediates suggest a detailed mechanism of dioxygen evolution based on changes in oxidization and protonation states and structural rearrangements of the oxomanganese cluster and surrounding water molecules. The catalytic reaction is consistent with substrate water molecules coordinated as terminal ligands to Mn(4) and calcium and requires the formation of an oxyl radical by deprotonation of the substrate water molecule ligated to Mn(4) and the accumulation of four oxidizing equivalents. The oxyl radical is susceptible to nucleophilic attack by a substrate water molecule initially coordinated to calcium and activated by two basic species, including CP43-R357 and the mu-oxo bridge between Mn(3) and Mn(4). The reaction is concerted with water ligand exchange, swapping the activated water by a water molecule in the second coordination shell of calcium.

Computational studies of the O(2)-evolving complex of photosystem II and biomimetic oxomanganese complexes.

In recent years, there has been considerable interest in studies of catalytic metal clusters in metalloproteins based on Density Functional Theory (DFT) quantum mechanics/molecular mechanics (QM/MM) hybrid methods. These methods explicitly include the perturbational influence of the surrounding protein environment on the structural/functional properties of the catalytic centers. In conjunction with recent breakthroughs in X-ray crystallography and advances in spectroscopic and biophysical studies, computational chemists are trying to understand the structural and mechanistic properties of the oxygen-evolving complex (OEC) embedded in photosystem II (PSII). Recent studies include the development of DFT-QM/MM computational models of the Mn(4)Ca cluster, responsible for photosynthetic water oxidation, and comparative quantum mechanical studies of biomimetic oxomanganese complexes. A number of computational models, varying in oxidation and protonation states and ligation of the catalytic center by amino acid residues, water, hydroxide and chloride have been characterized along the PSII catalytic cycle of water splitting. The resulting QM/MM models are consistent with available mechanistic data, Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction data and extended X-ray absorption fine structure (EXAFS) measurements. Here, we review these computational efforts focused towards understanding the catalytic mechanism of water oxidation at the detailed molecular level.

QM/MM computational studies of substrate water binding to the oxygen-evolving centre of photosystem II.

This paper reports computational studies of substrate water binding to the oxygen-evolving centre (OEC) of photosystem II (PSII), completely ligated by amino acid residues, water, hydroxide and chloride. The calculations are based on quantum mechanics/molecular mechanics hybrid models of the OEC of PSII, recently developed in conjunction with the X-ray crystal structure of PSII from the cyanobacterium Thermosynechococcus elongatus. The model OEC involves a cuboidal Mn3CaO4Mn metal cluster with three closely associated manganese ions linked to a single mu4-oxo-ligated Mn ion, often called the 'dangling manganese'. Two water molecules bound to calcium and the dangling manganese are postulated to be substrate molecules, responsible for dioxygen formation. It is found that the energy barriers for the Mn(4)-bound water agree nicely with those of model complexes. However, the barriers for Ca-bound waters are substantially larger. Water binding is not simply correlated to the formal oxidation states of the metal centres but rather to their corresponding electrostatic potential atomic charges as modulated by charge-transfer interactions. The calculations of structural rearrangements during water exchange provide support for the experimental finding that the exchange rates with bulk 18 O-labelled water should be smaller for water molecules coordinated to calcium than for water molecules attached to the dangling manganese. The models also predict that the S1-->S2 transition should produce opposite effects on the two water-exchange rates.

Quantum mechanics/molecular mechanics structural models of the oxygen-evolving complex of photosystem II.

The annual production of 260 Gtonnes of oxygen, during the process of photosynthesis, sustains life on earth. Oxygen is produced in the thylakoid membranes of green-plant chloroplasts and the internal membranes of cyanobacteria by photocatalytic water oxidation at the oxygen-evolving complex (OEC) of photosystem II (PSII). Recent breakthroughs in X-ray crystallography and advances in quantum mechanics/molecular mechanics (QM/MM) hybrid methods have enabled the construction of chemically sensible models of the OEC of PSII. The resulting computational structural models suggest the complete ligation of the catalytic center by amino acid residues, water, hydroxide and chloride, as determined from the intrinsic electronic properties of the oxomanganese core and the perturbational influence of the surrounding protein environment. These structures are found to be consistent with available mechanistic data, and are also compatible with X-ray diffraction models and extended X-ray absorption fine structure measurements. It is therefore conjectured that these OEC models are particularly relevant for the elucidation of the catalytic mechanism of water oxidation.

Computational studies of the primary phototransduction event in visual rhodopsin.

This Account addresses recent advances in the elucidation of the detailed molecular rearrangements due to the primary photochemical event in rhodopsin, a prototypical G-protein-coupled receptor (GPCR) responsible for the signal transmission cascade in the vertebrate vision process. The reviewed studies provide fundamental insight on long-standing problems regarding the assembly and function of the individual residues and bound water molecules that form the rhodopsin active site, a center that catalyzes the 11-cis/all-trans isomerization of the retinyl chromophore in the primary step of the phototransduction mechanism. Emphasis is placed on the authors' recent computational studies, based on state-of-the-art quantum mechanics/molecular mechanics (QM/MM) hybrid methods, addressing the structural refinement of the retinyl chromophore binding site in high-resolution X-ray structures of bovine visual rhodopsin, the energy storage mechanism, and the molecular origin of spectroscopic changes due to the primary photochemical event.

Density functional theory and DFT+U study of transition metal porphines adsorbed on Au(111) surfaces and effects of applied electric fields.

We apply density functional theory (DFT) and the DFT+U technique to study the adsorption of transition metal porphine molecules on atomistically flat Au(111) surfaces. DFT calculations using the Perdew-Burke-Ernzerhof exchange correlation functional correctly predict the palladium porphine (PdP) low-spin ground state. PdP is found to adsorb preferentially on gold in a flat geometry, not in an edgewise geometry, in qualitative agreement with experiments on substituted porphyrins. It exhibits no covalent bonding to Au(111), and the binding energy is a small fraction of an electronvolt. The DFT+U technique, parametrized to B3LYP-predicted spin state ordering of the Mn d-electrons, is found to be crucial for reproducing the correct magnetic moment and geometry of the isolated manganese porphine (MnP) molecule. Adsorption of Mn(II)P on Au(111) substantially alters the Mn ion spin state. Its interaction with the gold substrate is stronger and more site-specific than that of PdP. The binding can be partially reversed by applying an electric potential, which leads to significant changes in the electronic and magnetic properties of adsorbed MnP and approximately 0.1 A changes in the Mn-nitrogen distances within the porphine macrocycle. We conjecture that this DFT+U approach may be a useful general method for modeling first-row transition metal ion complexes in a condensed-matter setting.

Characterization of synthetic oxomanganese complexes and the inorganic core of the O2-evolving complex in photosystem II: evaluation of the DFT/B3LYP level of theory.

The capabilities and limitations of the Becke-3-Lee-Yang-Parr (B3LYP) hybrid density functional are investigated as applied to studies of mixed-valent multinuclear oxomanganese complexes. Benchmark calculations involve the analysis of structural, electronic and magnetic properties of di-, tri- and tetra-nuclear Mn complexes, previously characterized both chemically and spectroscopically, including the di-mu-oxo bridged dimers [Mn(III)Mn(IV)(mu-O)(2)(H(2)O)(2)(terpy)(2)](3+) (terpy=2,2':6,2''-terpyridine) and [Mn(III)Mn(IV)(mu-O)(2)(phen)(4)](3+) (phen=1,10-phenanthroline), the Mn trimer [Mn(3)O(4)(bpy)(4)(H(2)O)(2)](4+) (bpy=2,2'-bipyridine), and the tetramer [Mn(4)O(4)L(6)](+) with L=Ph(2)PO(2)(-). Furthermore, the density functional theory (DFT) B3LYP level is applied to analyze the hydrated Mn(3)O(4)CaMn cluster completely ligated by water, OH(-), Cl(-), carboxylate and imidazole ligands, analogous to the '3+1 Mn tetramer' of the oxygen-evolving complex of photosystem II. It is found that DFT/B3LYP predicts structural and electronic properties of oxomanganese complexes in pre-selected spin-electronic states in very good agreement with X-ray and magnetic experimental data, even when applied in conjunction with rather modest basis sets. However, it is conjectured that the energetics of low-lying spin-states is beyond the capabilities of the DFT/B3LYP level, constituting a limitation to mechanistic studies of multinuclear oxomanganese complexes where until now the performance of DFT/B3LYP has raised little concern.

QM/MM Models of the O2-Evolving Complex of Photosystem II.

This paper introduces structural models of the oxygen-evolving complex of photosystem II (PSII) in the dark-stable S1 state, as well as in the reduced S0 and oxidized S2 states, with complete ligation of the metal-oxo cluster by amino acid residues, water, hydroxide, and chloride. The models are developed according to state-of-the-art quantum mechanics/molecular mechanics (QM/MM) hybrid methods, applied in conjunction with the X-ray crystal structure of PSII from the cyanobacterium Thermosynechococcus elongatus, recently reported at 3.5 Šresolution. Manganese and calcium ions are ligated consistently with standard coordination chemistry assumptions, supported by biochemical and spectroscopic data. Furthermore, the calcium-bound chloride ligand is found to be bound in a position consistent with pulsed electron paramagnetic resonance data obtained from acetate-substituted PSII. The ligation of protein ligands includes monodentate coordination of D1-D342, CP43-E354, and D1-D170 to Mn(1), Mn(3), and Mn(4), respectively; η(2) coordination of D1-E333 to both Mn(3) and Mn(2); and ligation of D1-E189 and D1-H332 to Mn(2). The resulting QM/MM structural models are consistent with available mechanistic data and also are compatible with X-ray diffraction models and extended X-ray absorption fine structure measurements of PSII. It is, therefore, conjectured that the proposed QM/MM models are particularly relevant to the development and validation of catalytic water-oxidation intermediates.

QM/MM Study of the NMR Spectroscopy of the Retinyl Chromophore in Visual Rhodopsin.

The (1)H and (13)C nuclear magnetic resonance (NMR) spectra of the retinyl chromophore in rhodopsin are investigated by using quantum mechanics/molecular mechanics (QM/MM) hybrid methods at the density functional theory (DFT) B3LYP/6-31G*:Amber level of theory, in conjunction with the gauge independent atomic orbital (GIAO) method for the ab initio self-consistent-field (SCF) calculation of NMR chemical shifts. The study provides a first-principle interpretation of solid-state NMR experiments based on recently developed QM/MM computational models of rhodopsin and bathorhodopsin [Gascón, J. A.; Batista, V. S. Biophys. J. 2004, 87, 2931-2941]. The reported results are particularly relevant to the development and validation of atomistic models of prototypical G-protein-coupled receptors which regulate signal transduction across plasma membranes.