One- and Two-Electron Reductions in MiniSOG and their Implication in Catalysis.

The unconventional bioorthogonal catalytic activation of anticancer metal complexes by flavin and flavoproteins photocatalysis has been reported recently. The reactivity is based on a two-electron redox reaction of the photoactivated flavin. Furthermore, when it comes to flavoproteins, we recently reported that site mutagenesis can modulate and improve this catalytic activity in the mini Singlet Oxygen Generator protein (SOG). In this paper, we analyze the reductive half-reaction in different miniSOG environments by means of density functional theory. We report that the redox properties of flavin and the resulting reactivity of miniSOG is modulated by specific mutations, which is in line with the experimental results in the literature. This modulation can be attributed to the fundamental physicochemical properties of the system, specifically (i) the competition of single and double reduction of the flavin and (ii) the probability of electron transfer from the protein to the flavin. These factors are ultimately linked to the stability of flavin's electron-accepting orbitals in different coordination modes.

Flavin-mediated photoactivation of Pt(IV) anticancer complexes: computational insights on the catalytic mechanism.

The mechanism for the photocatalytic activation of Pt(IV) anticancer prodrugs by riboflavin in the presence of NADH has been investigated by DFT. In the first step of the reaction, the oxidation kinetics of NADH to afford the catalytically active riboflavin hydroquinone is dramatically favoured by generation of the flavin triplet excited state. In the triplet, formation of a π-π stacked adduct promotes the hydride transfer from NADH to riboflavin with an almost barrierless pathway (2.7 kcal mol-1). In the singlet channel, conversely, the process is endergonic and requires overcoming a higher activation energy (19.2 kcal mol-1). In the second half of the reaction, the reduction of the studied Pt(IV) complexes by riboflavin hydroquinone occurs via an inner sphere mechanism, displaying free energy barriers smaller than 10 kcal mol-1. Pt reduction by bioreductants such as NADH and ascorbate involve instead less stabilized transition states (22.2-38.3 kcal mol-1), suggesting that riboflavin hydroquinone is an efficient reducing agent for Pt(IV) derivatives in biological settings.

Experiment and Theory Clarify: Sc+ Receives One Oxygen Atom from SO2 to Form ScO+ , which Proves to be a Catalyst for the Hidden Oxygen-Exchange with SO2.

Using Fourier-transform ion cyclotron resonance mass spectrometry, it was experimentally determined that Sc+ in the highly diluted gas phase reacts with SO2 to form ScO+ and SO. By 18 O labeling, ScO+ was shown to play the role of a catalyst when further reacting with SO2 in a Mars-van Krevelen-like (MvK) oxygen exchange process, where a solid catalyst actively reacts with the substrate but emerges apparently unchanged at the end of the cycle. High-level quantum chemical calculations confirmed that the multi-step process to form ScO+ and SO is exoergic and that all intermediates and transition states in between are located energetically below the entrance level. The reaction starts from the triplet surface; although three spin-crossing points with minimal energy have been identified by computational means, there is no evidence that a two-state scenario is involved in the course of the reaction, by which the reactants could switch from the triplet to the singlet surface and back. Pivotal to the oxygen exchange reaction of ScO+ with SO2 is the occurrence of a highly symmetric four-membered cyclic intermediate by which two oxygen atoms become equivalent.

Computational approach to (ZnS)_{i} nanoclusters in ionic liquids.

Unique and attractive properties have been predicted for II-VI-type semiconductor nanoclusters within the field of nanotechnology. However, the low reaction kinetics within the usual solvents gives only thermodynamic control during their production process, making the obtention of different metastable polymorphs extremely difficult. The use of ionic liquids as solvents has been proposed to overcome this problem. Identifying how these nanoclusters are solvated within ionic liquids is fundamental if this strategy is to be pursued. While computational chemistry tools are best suited for this task, the complexity and size of the system requires a careful design of the simulation protocol, which is put forward in this work. Taking as reference the (ZnS)_{12} nanocluster and the [EMIM][EtSO_{4}] ionic liquid, we characterize the interactions between the nanoparticle and first solvation shell by density functional theory calculations, considering most of the solvent implicitly. The DFT results are consistent through different theory levels showing a strong interaction between the Zn atoms of the nanocluster and the [EtSO_{4}^{-}] anion of the ionic liquid. A more realistic representation of the system is obtained by classical MD calculations, for which various classical force fields were considered and several atomic interactions parameterized. This new set of parameters correctly describes the interaction of different (ZnS) nanoclusters, supporting its transferability. The resulting MD simulation shows the formation of a structured ionic liquid solvation shell around the nanocluster with no exchange of ions for at least 5 ns, in agreement with the strong interactions observed in the density functional theory calculations.

Enhancing the Photocatalytic Conversion of Pt(IV) Substrates by Flavoprotein Engineering.

Our recent work demonstrates that certain flavoproteins can catalyze the redox activation of Pt(IV) prodrug complexes under light irradiation. Herein, we used site-directed mutagenesis on the mini singlet oxygen generator (mSOG) to modulate the photocatalytic activity of this flavoprotein toward two model Pt(IV) substrates. Among the prepared mutants, Q103V mSOG displayed enhanced catalytic efficiency as a result of its longer triplet excited-state lifetime. This study shows, for the first time, that protein engineering can improve the catalytic capacity of a protein toward metal-containing substrates.

Comparison of Chemical and Interpretative Methods: the Carbon-Boron π-Bond as a Test Case*.

Quantum chemical calculations and NBO, ETS-NOCV, QTAIM and ELF interpretative approaches have been carried out on C-donor ligand-stabilized dihydrido borenium cations. Numerous descriptors of the C-B π-bond strength obtained from orbital localization, energy partitioning or topological methods as well as from structural and chemical parameters have been calculated for 39 C-donor ligands including N-heterocyclic carbenes and carbones. Comparison of the results allows the identification of relative and absolute descriptors of the π interaction. For both families of descriptors excellent correlations are obtained. This enables the establishment of a π-donation capability scale and shows that the interpretative methods, despite their conceptual differences, describe the same chemical properties. These results also reveal noticeable shortcomings in these popular methods, and some precautions that need to be taken to interpret their results adequately.

Revised Theoretical Model on Enantiocontrol in Phosphoric Acid Catalyzed H-Transfer Hydrogenation of Quinoline.

The enantioselective H-transfer hydrogenation of quinoline by Hantzsch ester is a relevant example of Brønsted acid catalyzed cascade reactions, with phosphoric acid being a privileged catalyst. The generally accepted mechanism points out the hydride transfer step as the rate- and stereodetermining step, however computations based on these models do not totally fit with experimental observations. We hereby present a computational study that enlightens the stereochemical outcome and quantitatively reproduces the experimental enantiomeric excesses in a series of H-transfer hydrogenations. Our calculations suggest that the high stereocontrol usually attained with BINOL-derived phosphoric acids results mostly from the steric constraints generated by an aryl substituent of the catalyst, which hinders the access of the Hantzsch ester to the catalytic site and enforces approach through a specific way. It relies on a new model involving the preferential assembly of one of the stereomeric complexes formed by the chiral phosphoric acid and the two reaction partners. The stereodetermining step thus occurs prior to the H-transfer step.

Riboflavin as a bioorthogonal photocatalyst for the activation of a PtIV prodrug.

Encouraging developments demonstrate that few transition metal and organometallic catalysts can operate in a bioorthogonal fashion and promote non-natural chemistry in living systems by minimizing undesired side reactions with cellular components. These catalytic processes have potential for applications in medicinal chemistry and chemical biology. However, the stringent conditions of the cell environment severely limit the number of accessible metal catalysts and exogenous reactions. Herein, we report an unorthodox approach and a new type of bioorthogonal catalytic reaction, in which a metal complex is an unconventional substrate and an exogenous biological molecule acts as a catalyst. In this reaction, riboflavin photocatalytically converts a PtIV prodrug into cisplatin within the biological environment. Due to the catalytic activity of riboflavin, cisplatin-like apoptosis is induced in cancer cells under extremely low doses of light, potentially preventing systemic off-target reactions. Photocatalytic and bioorthogonal turnover of PtIV into PtII species is an attractive strategy to amplify the antineoplastic action of metal-based chemotherapeutics with spatio-temporal control.

Heteroleptic, two-coordinate [M(NHC){N(SiMe3)2}] (M = Co, Fe) complexes: synthesis, reactivity and magnetism rationalized by an unexpected metal oxidation state.

The linear, two-coordinate and isostructural heteroleptic [M(IPr){N(SiMe3)2}] (IPr = 1,3-bis(diisopropylphenyl)-imidazol-2-ylidene), formally MI complexes (M = Co, 3; Fe, 4) were obtained by the reduction of [M(IPr)Cl{N(SiMe3)2}] with KC8, or [Co(IPr){N(SiMe3)2}2] with mes*PH2, mes* = 2,4,6-tBu3C6H2. The magnetism of 3 and 4 implies CoII and FeII centres coupled to one ligand-delocalized electron, in line with XPS and XANES data; the ac susceptibility of 4 detected a pronounced frequency dependence due to slow magnetization relaxation. Reduction of [Fe(IPr)Cl{N(SiMe3)2}] with excess KC8 in toluene gave the heteronuclear 'inverse-sandwich' Fe-K complex 7, featuring η6-toluene sandwiched between one Fe0 and one K+ centre.

Ionic liquids as solvents of polar and non-polar solutes: affinity and coordination.

The use of ionic liquids (ILs) as highly tuneable solvents requires a deep understanding of the intermolecular interactions they can establish with the solutes. In the present work, we study the solvation patterns of two small but highly important molecules in the framework of IL properties and applications, namely H2O and CO2. Density functional theory (DFT) and ab initio molecular dynamics (AIMD) techniques are used for a systematic study of the interactions established between the solute and the solvent, identifying the influence of the non specific and specific interactions on the affinity of the IL for the solute, and how these interactions change with the surrounding environment. The nature, spatial distribution and strength of these interactions are described by means of topological analysis of the electronic density of the system.

Estimating π binding energy of N-heterocyclic carbenes: the role of polarization.

In this work, the tuneability of the π acceptor or donor properties of a set of N-heterocyclic carbenes (NHCs) with a wide spectrum of electronic characteristics is established by means of density functional theory and energy decomposition analysis (EDA) tools. Even though the main orbital interaction contribution to the NHC coordination is the σ donation, a significant contribution of the π interactions to the bond is observed. By means of carefully selected coordination sites, different contributions to the π interactions could be identified and isolated. It includes not only the well known back donation and donation interactions, but also the intrafragment polarization, which has not been considered in previous studies. This can be obtained through the use of the extended transition state method for EDA combined with the natural orbitals for chemical valence and the constrained space orbital variation analysis. The contributions vary with the position of the heteroatoms and the presence of exocyclic substituents; the donation/backdonation π interactions between NHC and the coordination site can range between 2 and 61% of the total π orbital interactions, while the rest is owed to intrafragment polarization. Our results do not only contribute to the understanding of the electronic structure of NHC-based complexes, giving ways to improve their catalytic properties, but also provide comprehension on the modelization methods used to study their donor-acceptor interactions.

Unprecedented directed lateral lithiations of tertiary carbons on NHC platforms.

Unexpected and unprecedented directed remote lateral lithiation at one CH(CH3)2 of the 3-(2,6-di-isopropylphenyl) wingtip took place upon the reaction of functionalised N-heterocyclic carbene-type molecules with excess of LiCH2SiMe3, leading to dilithiated dianionic 4-amido-N-heterocyclic carbenes. DFT calculations show that the nature of the isolated species are under thermodynamic control.

Mapping the affinity of aluminum(III) for biophosphates: interaction mode and binding affinity in 1 : 1 complexes.

The interaction of aluminum with biomolecular building blocks is a topic of interest as a first step to understand the potential toxic effects of aluminum in biosystems. Among the different molecules that aluminum can bind in a biological environment, phosphates are the most likely ones, due to their negatively charged nature. In the present paper, we combined DFT quantum mechanical calculations with the implicit solvent effect in order to characterize the interaction of Al(III) with these molecules. An extended set composed of a total of 59 structures was investigated, which includes various types of phosphates (monoester, diester, triester-phosphates) and various phosphate units (mono-, di- and tri-phosphate), considering various charge and protonation states, and different binding modes. The goal is to unveil the preferential interaction mode of Al(III) with phosphates in 1 : 1 complexes. Our results reveal that Al(III) prefers to form dicoordinated complexes with two phosphates, in which the interaction with each of the phosphates is of monodentate character. Our results also suggest a high affinity for binding basic phosphate groups, pointing to ATP, phosphorylated peptides, and basic diphosphates (such as 2,3-DPG) as strong aluminum chelators.

DNA aptamers are functional molecular recognition sensors in protic ionic liquids.

The function and structural changes of an AMP molecular aptamer beacon and its molecular recognition capacity for its target, adenosine monophosphate (AMP), was systematically explored in solution with a protic ionic liquid, ethylammonium nitrate (EAN). It could be proven that up to 2 M of EAN in TBS buffer, the AMP molecular aptamer beacon was still capable of recognizing AMP while also maintaining its specificity. The specificity was proven by using the guanosine monophosphate (GMP) as target; GMP is structurally similar to AMP but was not recognized by the aptamer. We also found that in highly concentrated EAN solutions the overall amount of double stranded DNA formed, as well as its respective thermal stability, diminished gradually, but surprisingly the hybridization rate (kh ) of single stranded DNA was significantly accelerated in the presence of EAN. The latter may have important implications in DNA technology for the design of biosensing and DNA-based nanodevices in nonconventional solvents, such as ionic liquids.

Aluminium in biological environments: a computational approach.

The increased availability of aluminium in biological environments, due to human intervention in the last century, raises concerns on the effects that this so far "excluded from biology" metal might have on living organisms. Consequently, the bioinorganic chemistry of aluminium has emerged as a very active field of research. This review will focus on our contributions to this field, based on computational studies that can yield an understanding of the aluminum biochemistry at a molecular level. Aluminium can interact and be stabilized in biological environments by complexing with both low molecular mass chelants and high molecular mass peptides. The speciation of the metal is, nonetheless, dictated by the hydrolytic species dominant in each case and which vary according to the pH condition of the medium. In blood, citrate and serum transferrin are identified as the main low molecular mass and high molecular mass molecules interacting with aluminium. The complexation of aluminium to citrate and the subsequent changes exerted on the deprotonation pathways of its tritable groups will be discussed along with the mechanisms for the intake and release of aluminium in serum transferrin at two pH conditions, physiological neutral and endosomatic acidic. Aluminium can substitute other metals, in particular magnesium, in protein buried sites and trigger conformational disorder and alteration of the protonation states of the protein's sidechains. A detailed account of the interaction of aluminium with proteic sidechains will be given. Finally, it will be described how alumnium can exert oxidative stress by stabilizing superoxide radicals either as mononuclear aluminium or clustered in boehmite. The possibility of promotion of Fenton reaction, and production of hydroxyl radicals will also be discussed.

First principle approach to solvation by methylimidazolium-based ionic liquids.

Understanding the nature of the inter- and intramolecular interactions of solutes and ionic liquid (IL) ion pairs from an electronic point of view is necessary for explaining the mechanisms behind the selectivity of ILs toward a certain solute. Due to the complexity of the underlying physicochemical interactions, and aiming at a reliable representation of the solute-IL interactions, the model system chosen in this work is formed by one single ion pair and the solute of interest, in the gas phase. Ab initio molecular dynamics (MD) techniques are used for ensuring a complete scan of the potential energy surface. A representative number of structures extracted from this trajectory are optimized using more sophisticated DFT methods. Posterior bond analysis (with natural bonding orbitals (NBO), and Morokuma-like energy partition) provide a detailed picture of the solute-IL bond nature for a set of various solutes, anions, and cations, to find a relationship between the gas phase electronic characteristics and the experimentally observed behavior. The approximation to the ILs solvation properties employing this very basic model shows that, on one side, the specific interaction of the solute with methylimidazolium-based IL is a reliable indication of the overall affinity between the bulk IL and the solute, and can be considered a predictive tool for the bulk behavior. Furthermore, the systematic study carried out has permitted the rational comprehension of such properties and thus permits us to extend it to other systems.

Quantum chemical assessment of the binding energy of CuO+.

We present a detailed theoretical investigation on the dissociation energy of CuO(+), carried out by means of coupled cluster theory, the multireference averaged coupled pair functional (MR-ACPF) approach, diffusion quantum Monte Carlo (DMC), and density functional theory (DFT). At the respective extrapolated basis set limits, most post-Hartree-Fock approaches agree within a narrow error margin on a D(e) value of 26.0 kcal mol(-1) [coupled-cluster singles and doubles level augmented by perturbative triples corrections, CCSD(T)], 25.8 kcal mol(-1) (CCSDTQ via the high accuracy extrapolated ab initio thermochemistry protocol), and 25.6 kcal mol(-1) (DMC), which is encouraging in view of the disaccording data published thus far. The configuration-interaction based MR-ACPF expansion, which includes single and double excitations only, gives a slightly lower value of 24.1 kcal mol(-1), indicating that large basis sets and triple excitation patterns are necessary ingredients for a quantitative assessment. Our best estimate for D(0) at the CCSD(T) level is 25.3 kcal mol(-1), which is somewhat lower than the latest experimental value (D(0) = 31.1 ± 2.8 kcal mol(-1)[semicolon] reported by the Armentrout group) [Int. J. Mass Spectrom. 182/183, 99 (1999)]. These highly correlated methods are, however, computationally very demanding, and the results are therefore supplemented with those of more affordable DFT calculations. If used in combination with moderately-sized basis sets, the M05 and M06 hybrid functionals turn out to be promising candidates for studies on much larger systems containing a [CuO](+) core.

Ligand effects on the [Cu(PhO)(PhOH)]+ redox active complex.

Under gas phase conditions, the [Cu(PhO)(PhOH)](+) complex is composed of copper(I), a phenoxy radical bound via the oxygen atom, and a phenol bound via the aromatic ring. Effects of additional ligand coordination on the molecular and electronic structure of the complex [Cu(PhO)(PhOH)](+) are investigated by mass spectrometric and quantum chemical means for [Cu(PhO)L](+) (L = H(2)O, CH(3)OH, tetrahydrofuran, NH(3), pyridine, imidazole, 1,2-dimethoxyethylene, N,N,N',N'-tetramethylethylenediamine, pyrrole, and thiophene) and [Cu(PhO)(PhOH)L(n)](+) (L = H(2)O, NH(3), and 4-methylimidazole) models. The nature and number of additional ligands critically influences the spin distribution in the complex, which is sensitively reflected by the phenoxy CO stretching mode.

Quantum Monte Carlo study of the ground state and low-lying excited states of the scandium dimer.

A large set of electronic states of scandium dimer has been calculated using high-level theoretical methods such as quantum diffusion Monte Carlo (DMC), complete active space perturbation theory as implemented in GAMESS-US, coupled-cluster singles, doubles, and triples, and density functional theory (DFT). The 3 Sigma u and 5 Sigma u states are calculated to be close in energy in all cases, but whereas DFT predicts the 5 Sigma u state to be the ground state by 0.08 eV, DMC and CASPT2 calculations predict the 3 Sigma u to be more stable by 0.17 and 0.16 eV, respectively. The experimental data available are in agreement with the calculated frequencies and dissociation energies of both states, and therefore we conclude that the correct ground state of scandium dimer is the 3 Sigma u state, which breaks with the assumption of a 5 Sigma u ground state for scandium dimer, believed throughout the past decades.

Protein side chains facilitate Mg/Al exchange in model protein binding sites.

Among the most frequent protein binding sites served by Mg(II), we identify those which have higher affinity towards Al(III). We also estimate the free energies of metal exchange for all these binding sites taking into account solvent effects explicitly. The obtained results show that thermodynamically favored Mg(II)/Al(III) exchange reactions take place at a number of these metal binding sites, which could possibly be related to some dysfunctions of Mg(II)-dependent biological processes. Additionally, they shed light on the molecular basis of the toxicity of Al(III) in living organisms.