Aurélien de la Lande

Multipoint molecular recognition within a calix[6]arene funnel complex

A multipoint recognition system based on a calix[6]arene is described. The calixarene core is decorated on alternating aromatic subunits by 3 imidazole arms at the small rim and 3 aniline groups at the large rim. This substitution pattern projects the aniline nitrogens toward each other when Zn(II) binds at the Tris-imidazole site or when a proton binds at an aniline. The XRD structure of the monoprotonated complex having an acetonitrile molecule bound to Zn(II) in the cavity revealed a constrained geometry at the metal center reminiscent of an entatic state. Computer modeling suggests that the aniline groups behave as a tritopic monobasic site in which only 1 aniline unit is protonated and interacts with the other 2 through strong hydrogen bonding. The metal complex selectively binds a monoprotonated diamine vs. a monoamine through multipoint recognition: coordination to the metal ion at the small rim, hydrogen bonding to the calix-oxygen core, CH/π interaction within the cavitys aromatic walls, and H-bonding to the anilines at the large rim.

Theoretical modelling of tripodal CuN3 and CuN4 cuprous complexes interacting with O2, CO or CH3CN

Dioxygen binding at copper enzymatic sites is a fundamental aspect of the catalytic activity observed in many biological systems such as the monooxygenases, especially peptidylglycine α-hydroxylating monooxygenase (PHM), in which two mononuclear CuI sites are involved. Biomimetic models have been developed: dipods, tripods, and, more recently, functionalized calixarenes. The modelling of calixarene systems, although not unreachable for theory yet, requires, however, a number of preliminary investigations to ensure proper calibrations if relevant description of the metal–ligand interaction at the hybrid quantum mechanical/molecular mechanics levels of theory is the aim. In this paper, we report quantum chemistry investigations on a coherent series of representative cuprous tripodal species characterized by (1) monodentate ligands [Cu(ImH)3]+ (where ImH is imidazole), [Cu(MeNH2)3]+ and [Cu(MeNH2)4]+ , (2) neutral tripodal ligands [CuCH(ImH)3]+, [Cu(tren)]+ [where tren is tris(2-aminoethyl)amine], and [Cu(trenMe3)]+ [where trenMe3 is tris(2-methylaminoethyl)amine] and (3) a hydrido-tris(pyrazolyl)borate [CuBH(Pyra)3]. The structures of these complexes, the coordination mode (η2 side-on or η1 end-on) of O2 to CuI and the charge transfer from the metal to dioxygen have been computed. For some systems, the coordination by CH3CN and CO is also reported. Beyond results relative to structural properties, an interesting feature is that it is possible to build from computational results only a set of abacuses linking the ν(16O–16O) vibrational frequency of the coordinated O2 molecule to the O–O bond length or to the net charge of the O2 moiety. Such abacuses may help experimentalists in distinguishing between the four possible ways of binding O2 to CuN3 and CuN4 cuprous centres, namely (1) end-on triplet states, (2) side-on triplet states, (3) end-on singlet states and (4) side-on singlet states. These abacuses are extended to three tripods obtained by the substitution of one nitrogen atom by either a phosphorus or a sulphur atom. Moreover, it is shown that any factor favouring pyramidalization at copper favours charge transfer and thus coordination of the incoming O2 moiety. All these allow insight into the coordination mode of O2 and into the charge transfer from CuI in site CuM of PHM.

Selective recognition of fluoride anion in water by a copper(II) center embedded in a hydrophobic cavity

The ability of a water-soluble pentacationic calix[6]arene-based CuII complex to bind anions in water has been explored. Quite remarkably, the complex exhibits strong and selective fluoride binding in the pH range of 6–7. The binding constant at pH 5.9 was evaluated to be 85u2006000 M−1, which is one of the highest values ever reported for a fluoride probe in water and at this pH. The complex also binds chloride ions, but 1000 times less efficiently. The combination of the calix[6]arene hydrophobic cavity with the CuII complex, presenting its labile site in the endo position, is the reason for the selective recognition process. The single crystal X-ray structure of the organo-soluble parent complex revealed a strong interaction between the coordinated fluoride anion and a hosted CHCl3 solvent molecule. Molecular modeling applying an aqueous environment suggests that a water cluster, [F·H2O·H2O]−, is the species recognized by the host, which provides an appropriate environment for the stabilization of such a hydrated fluoride guest/species.

Directional control and supramolecular protection allowing the chemo- and regioselective transformation of a triamine.

A Zn(II)-funnel complex based on a calix[6]arene ligand decorated with three tris(imidazolyl) arms at one end of the cone and three NH(2) substituents at the other end, acts as a multipoint recognition host for polyfunctionalized guests. The selectivity is ensured by coordination to Zn(II), CH-pi interaction within the calix cone, and H-bonding at both rims of the cavity. As a result of these multiple interactions, the host can wrap and orient an unsymmetrical triamine guest with a high selectivity. Furthermore, a proton-monitored switch between the regio-isomeric adducts allows reversible inversion of the directionality of the system. Thanks to this directional control, the regioselective mono-carbamoylation of the unsymmetrical triamine guest was successfully achieved on a preparative scale. This case study shows that a funnel-like receptor can be used as a supramolecular protecting tool allowing a transformation which would be impracticable with conventional covalent chemistry.

Singlet-triplet gaps in large multireference systems: Spin-flip-driven alternatives for bioinorganic modeling

The proper description of low-spin states of open-shell systems, which are commonly encountered in the field of bioinorganic chemistry, rigorously requires using multireference ab initio methodologies. Such approaches are unfortunately very CPU-time consuming as dynamic correlation effects also have to be taken into account. The broken-symmetry unrestricted (spin-polarized) density functional theory (DFT) technique has been widely employed up to now to bypass that drawback, but despite a number of relative successes in the determination of singlet-triplet gaps, this framework cannot be considered as entirely satisfactory. In this contribution, we investigate some alternative ways relying on the spin-flip time-dependent DFT approach [Y. Shao et al. J. Chem. Phys. 118, 4807 (2003)]. Taking a few well-documented copper-dioxygen adducts as examples, we show that spin-flip (SF)-DFT computed singlet-triplet gaps compare very favorably to either experimental results or large-scale CASMP2 computations. Moreover, it is shown that this approach can be used to optimize geometries at a DFT level including some multireference effects. Finally, a clear-cut added value of the SF-DFT computations is drawn: if pure ab initio data are required, then the electronic excitations revealed by SF-DFT can be considered in designing dramatically reduced zeroth-order variational spaces to be used in subsequent multireference configuration interaction or multireference perturbation treatments.

Investigation of the hydroxylation mechanism of noncoupled copper oxygenases by ab initio molecular dynamics simulations.

In Nature, the family of copper monooxygenases comprised of peptidylglycine α-hydroxylating monooxygenase (PHM), dopamine β-monooxygenase (DβM), and tyramine β-monooxygenase (TβM) is known to perform dioxygen-dependent hydroxylation of aliphatic C-H bonds by using two uncoupled metal sites. In spite of many investigations, including biochemical, chemical, and computational, details of the C-H bond oxygenation mechanism remain elusive. Herein we report an investigation of the mechanism of hydroxylation by PHM by using hybrid quantum/classical potentials (i.e., QM/MM). Although previous investigations using hybrid QM/MM techniques were restricted to geometry optimizations, we have carried out ab initio molecular dynamics simulations in order to include the intrinsic flexibility of the active sites in the modeling protocol. The major finding of this study is an extremely fast rebound step after the initial hydrogen-abstraction step promoted by the cupric-superoxide adduct. The hydrogen-abstraction/rebound sequence leads to the formation of an alkyl hydroperoxide intermediate. Long-range electron transfer from the remote copper site subsequently triggers its reduction to the hydroxylated substrate. We finally show two reactivity consequences inherent in the new mechanistic proposal, the investigation of which would provide a means to check its validity by experimental means.

New insights into the mechanism of electron transfer within flavohemoglobins: tunnelling pathways, packing density, thermodynamic and kinetic analyses

Flavohemoglobins (FlavoHb) are metalloenzymes catalyzing the reaction of nitric oxide dioxygenation. The iron cation of the heme group needs to be preliminarily reduced to the ferrous state to be catalytically competent. This reduction is triggered by a flavin adenine dinucleotide (FAD) prosthetic group which is localized in a distinct domain of the protein. In this paper we obtain new insights into the internal long range electron transfer (over ca. 12 Å) using a combination of experimental and computational approaches. Employing a time-resolved pulse radiolysis technique we report the first direct measurement of the FADH˙→ HemeFe(III) electron transfer rate. A rate constant of (6.8 ± 0.5) × 10(3) s(-1) is found. A large panel of computational approaches are used to provide the first estimation of the thermodynamic characteristics of the internal electron transfer step within flavoHb: both the driving force and the reorganization energy are estimated as a function of the protonated state of the flavin semi-quinone. We also report an analysis of the electron pathways involved in the tunnelling of the electron through the aqueous interface between the globin and the flavin domains.

Topological analyses of time-dependent electronic structures: application to electron-transfers in methionine enkephalin

We have studied electron transfers (ET) between electron donors and acceptors, taking as illustrative example the case of ET in methionine enkephalin. Recent pulse and gamma radiolysis experiments suggested that an ultrafast ET takes place from the C-terminal tyrosine residue to the N-terminal, oxidized, methionine residue. According to standard theoretical frameworks like the Marcus theory, ET can be decomposed into two successive steps: i) the achievement through thermal fluctuations, of a set of nuclear coordinates associated with degeneracy of the two electronic states, ii) the electron tunneling from the donor molecular orbital to the acceptor molecular orbital. Here, we focus on the analysis of the time-dependent electronic dynamics during the tunneling event. This is done by extending the approaches based on the topological analyses of stationary electronic density and of the electron localization function (ELF) to the time-dependent domain. Furthermore, we analyzed isosurfaces of the divergence of the current density, showing the paths that are followed by the tunneling electron from the donor to the acceptor. We show how these functions can be calculated with constrained density functional theory. Beyond this work, the topological tools used here can open up new opportunities for the electronic description in the time-dependent domain.

Progress and challenges in simulating and understanding electron transfer in proteins.

This Review presents an overview of the most common numerical simulation approaches for the investigation of electron transfer (ET) in proteins. We try to highlight the merits of the different approaches but also the current limitations and challenges. The article is organized into three sections. Section 2 deals with direct simulation algorithms of charge migration in proteins. Section 3 summarizes the methods for testing the applicability of the Marcus theory for ET in proteins and for evaluating key thermodynamic quantities entering the reaction rates (reorganization energies and driving force). Recent studies interrogating the validity of the theory due to the presence of non-ergodic effects or of non-linear responses are also described. Section 4 focuses on the tunneling aspects of electron transfer. How can the electronic coupling between charge transfer states be evaluated by quantum chemistry approaches and rationalized? What interesting physics regarding the impact of protein dynamics on tunneling can be addressed? We will illustrate the different sections with examples taken from the literature to show what types of system are currently manageable with current methodologies. We also take care to recall what has been learned on the biophysics of ET within proteins thanks to the advent of atomistic simulations.

Theoretical estimation of redox potential of biological quinone cofactors

Redox potentials are essential to understand biological cofactor reactivity and to predict their behavior in biological media. Experimental determination of redox potential in biological system is often difficult due to complexity of biological media but computational approaches can be used to estimate them. Nevertheless, the quality of the computational methodology remains a key issue to validate the results. Instead of looking to the best absolute results, we present here the calibration of theoretical redox potential for quinone derivatives in water coupling QMu2009+u2009MM or QM/MM scheme. Our approach allows using low computational cost theoretical level, ideal for long simulations in biological systems, and determination of the uncertainties linked to the calculations.