Machine Learning-Enhanced Quantum Chemistry-Assisted Refinement of the Active Site Structure of Metalloproteins.

Understanding the fine structural details of inhibitor binding at the active site of metalloenzymes can have a profound impact on the rational drug design targeted to this broad class of biomolecules. Structural techniques such as NMR, cryo-EM, and X-ray crystallography can provide bond lengths and angles, but the uncertainties in these measurements can be as large as the range of values that have been observed for these quantities in all the published structures. This uncertainty is far too large to allow for reliable calculations at the quantum chemical (QC) levels for developing precise structure-activity relationships or for improving the energetic considerations in protein-inhibitor studies. Therefore, the need arises to rely upon computational methods to refine the active site structures well beyond the resolution obtained with routine application of structural methods. In a recent paper, we have shown that it is possible to refine the active site of cobalt(II)-substituted MMP12, a metalloprotein that is a relevant drug target, by matching to the experimental pseudocontact shifts (PCS) those calculated using multireference ab initio QC methods. The computational cost of this methodology becomes a significant bottleneck when the starting structure is not sufficiently close to the final one, which is often the case with biomolecular structures. To tackle this problem, we have developed an approach based on a neural network (NN) and a support vector regression (SVR) and applied it to the refinement of the active site structure of oxalate-inhibited human carbonic anhydrase 2 (hCAII), another prototypical metalloprotein target. The refined structure gives a remarkably good agreement between the QC-calculated and the experimental PCS. This study not only contributes to the knowledge of CAII but also demonstrates the utility of combining machine learning (ML) algorithms with QC calculations, offering a promising avenue for investigating other drug targets and complex biological systems in general.

High-Spin and Reactive Fe13 Cluster with Exposed Metal Sites.

Atomically defined large metal clusters have applications in new reaction development and preparation of materials with tailored properties. Expanding the synthetic toolbox for reactive high nuclearity metal complexes, we report a new class of Fe clusters, Tp*4 W4 Fe13 S12 , displaying a Fe13 core with M-M bonds that has precedent only in main group and late metal chemistry. M13 clusters with closed shell electron configurations can show significant stability and have been classified as superatoms. In contrast, Tp*4 W4 Fe13 S12 displays a large spin ground state of S=13. This compound performs small molecule activations involving the transfer of up to 12 electrons resulting in significant cluster rearrangements.

Toward Opto-Structural Correlation to Investigate Luminescence Thermometry in an Organometallic Eu(II) Complex.

Lanthanide-based luminescent materials have unique properties and are well-studied for many potential applications. In particular, the characteristic 5d → 4f emission of divalent lanthanide ions such as EuII allows for tunability of the emissive properties via modulation of the coordination environment. We report the synthesis and photoluminescence investigation of pentamethylcyclopentadienyleuropium(II) tetrahydroborate bis(tetrahydrofuran) dimer (1), the first example of an organometallic, discrete molecular EuII band-shift luminescence thermometer. Complex 1 exhibits an absolute sensitivity of 8.2 cm-1 K-1 at 320 K, the highest thus far observed for a lanthanide-based band-shift thermometer. Opto-structural correlation via variable-temperature single-crystal X-ray diffraction and fluorescence spectroscopy allows rationalization of the remarkable thermometric luminescence of complex 1 and reveals the significant potential of molecular EuII compounds in luminescence thermometry.

Observability of Paramagnetic NMR Signals at over 10 000 ppm Chemical Shifts.

We report an experimental observation of 31 P NMR resonances shifted by over 10 000 ppm (meaning percent range, and a new record for solutions), and similar 1 H chemical shifts, in an intermediate-spin square planar ferrous complex [tBu (PNP)Fe-H], where PNP is a carbazole-based pincer ligand. Using a combination of electronic structure theory, nuclear magnetic resonance, magnetometry, and terahertz electron paramagnetic resonance, the influence of magnetic anisotropy and zero-field splitting on the paramagnetic shift and relaxation enhancement is investigated. Detailed spin dynamics simulations indicate that, even with relatively slow electron spin relaxation (T1 ≈10-11  s), it remains possible to observe NMR signals of directly metal-bonded atoms because pronounced rhombicity in the electron zero-field splitting reduces nuclear paramagnetic relaxation enhancement.

A High-Resolution View of the Coordination Environment in a Paramagnetic Metalloprotein from its Magnetic Properties.

Metalloproteins constitute a significant fraction of the proteome of all organisms and their characterization is critical for both basic sciences and biomedical applications. A large portion of metalloproteins bind paramagnetic metal ions, and paramagnetic NMR spectroscopy has been widely used in their structural characterization. However, the signals of nuclei in the immediate vicinity of the metal center are often broadened beyond detection. In this work, we show that it is possible to determine the coordination environment of the paramagnetic metal in the protein at a resolution inaccessible to other techniques. Taking the structure of a diamagnetic analogue as a starting point, a geometry optimization is carried out by fitting the pseudocontact shifts obtained from first principles quantum chemical calculations to the experimental ones.

Metal-organic magnets with large coercivity and ordering temperatures up to 242°C.

Magnets derived from inorganic materials (e.g., oxides, rare-earth-based, and intermetallic compounds) are key components of modern technological applications. Despite considerable success in a broad range of applications, these inorganic magnets suffer several drawbacks, including energetically expensive fabrication, limited availability of certain constituent elements, high density, and poor scope for chemical tunability. A promising design strategy for next-generation magnets relies on the versatile coordination chemistry of abundant metal ions and inexpensive organic ligands. Following this approach, we report the general, simple, and efficient synthesis of lightweight, molecule-based magnets by postsynthetic reduction of preassembled coordination networks that incorporate chromium metal ions and pyrazine building blocks. The resulting metal-organic ferrimagnets feature critical temperatures up to 242°C and a 7500-oersted room-temperature coercivity.

Revisiting dithiadiaza macrocyclic chelators for copper-64 PET imaging.

Synthesis and characterisation of a dithiadiaza chelator NSNS2A, as well as copper complexes thereof are reported in this paper. Solution structures of copper(i/ii) complexes were calculated using density functional theory (DFT) and validated by both NMR and EPR spectroscopy. DFT calculations revealed a switch in the orientation of tetragonal distortion upon protonation, which might be responsible for poor stability of the Cu(II)NSNS2A complex in aqueous media, whilst the same switch in tetragonal distortion was experimentally observed by changing the solvent. The chelator was radiolabeled with 64Cu and evaluated using PET/MRI in rats. Despite a favorable redox potential to stabilize the cuprous state in vivo, the 64Cu(II)NSNS2A complex showed suboptimal stability compared to its tetraazamacrocyclic analogue, 64Cu(TE2A), with a significant 64Cu uptake in the liver.

A Barrel-Shaped Metal-Organic Blue-Box Analogue with Photo-/Redox-Switchable Behavior.

Donor-acceptor interactions are ubiquitous in the design and understanding of host-guest complexes. Despite their non-covalent nature, they can readily dictate the self-assembly of complex architectures. Here, a photo-/redox-switchable metal-organic nanocapsule is presented, which was assembled by using lanthanide ions and viologen building blocks, by relying on such donor-acceptor interactions. The potential of this unique barrel-shaped structure is highlighted for the encapsulation of suitable electron donors, akin to the well-investigated "blue-box" macrocycles. The light-triggered reduction of the viologen units has been investigated by single-crystal-to-single-crystal X-ray diffraction experiments, complemented by magnetic, optical, and solid-state electrochemical characterizations. Density functional theory (DFT) calculations were employed to suggest the most likely electron donor in the light-triggered reduction of the viologen-based ligand.

How the Ligand Field in Lanthanide Coordination Complexes Determines Magnetic Susceptibility Anisotropy, Paramagnetic NMR Shift, and Relaxation Behavior.

Complexes of lanthanide(III) ions are being actively studied because of their unique ground and excited state properties and the associated optical and magnetic behavior. In particular, they are used as emissive probes in optical spectroscopy and microscopy and as contrast agents in magnetic resonance imaging (MRI). However, the design of new complexes with specific optical and magnetic properties requires a thorough understanding of the correlation between molecular structure and electric and magnetic susceptibilities, as well as their anisotropies. The traditional Judd-Ofelt-Mason theory has failed to offer useful guidelines for systematic design of emissive lanthanide optical probes. Similarly, Bleaney's theory of magnetic anisotropy and its modifications fail to provide accurate detail that permits new paramagnetic shift reagents to be designed rather than discovered.A key determinant of optical and magnetic behavior in f-element compounds is the ligand field, often considered as an electrostatic field at the lanthanide created by the ligands. The resulting energy level splitting is a sensitive function of several factors: the nature and polarizability of the whole ligand and its donor atoms; the geometric details of the coordination polyhedron; the presence and extent of solvent interactions; specific hydrogen bonding effects on donor atoms and the degree of supramolecular order in the system. The relative importance of these factors can vary widely for different lanthanide ions and ligands. For nuclear magnetic properties, it is both the ligand field splitting and the magnetic susceptibility tensor, notably its anisotropy, that determine paramagnetic shifts and nuclear relaxation enhancement.We review the factors that control the ligand field in lanthanide complexes and link these to aspects of their utility in magnetic resonance and optical emission spectroscopy and imaging. We examine recent progress in this area particularly in the theory of paramagnetic chemical shift and relaxation enhancement, where some long-neglected effects of zero-field splitting, magnetic susceptibility anisotropy, and spatial distribution of lanthanide tags have been accommodated in an elegant way.

A heteroleptic diradical Cr(iii) complex with extended spin delocalization and large intramolecular magnetic exchange.

Successive chemical reductions of the heteroleptic complex [(tpy)CrIII(tphz)]3+ (tpy = terpyridine; tphz = tetrapyridophenazine) give rise to the mono- and di-radical redox isomers, [(tpy)CrIII(tphz˙-)]2+ and [(tpy˙-)CrIII(tphz˙-)]+, respectively. As designed, the optimized overlap of the involved magnetic orbitals leads to extremely strong magnetic interactions between the S = 3/2 metal ion and S = 1/2 radical spins, affording well isolated ST = 1 and ST = 1/2 ground states at room temperature.

Exploring the dual functionality of an ytterbium complex for luminescence thermometry and slow magnetic relaxation.

We present a comprehensive investigation of the magnetic and optical properties of an ytterbium complex, which combines two desirable and practical features into a single molecular system. Based upon YbIII ions that promote near-infrared optical activity and a chemical backbone that is ideal for an in-depth understanding of the magnetic behaviour, we have designed a multifunctional opto-magnetic species that operates as a luminescent thermometer and as a single-molecule magnet (SMM). Our magnetic investigations, in conjunction with ab initio calculations, reveal one of the highest energy barriers reported for an YbIII-based complex. Moreover, we correlate this anisotropic barrier with the emission spectrum of the compound, wherein we provide a complete assignment of the energetic profile of the complex. Such studies lay the foundation for the design of exciting multi-faceted materials that are able to retain information at the single-molecule level and possess built-in thermal self-monitoring capabilities.

Periodic trends and hidden dynamics of magnetic properties in three series of triazacyclononane lanthanide complexes.

In three structurally related series of nine-coordinate lanthanide(iii) complexes (Ln = Tb, Dy, Ho, Er, Tm and Yb) based on triazacyclononane, solution NMR studies and DFT/CASSCF calculations have provided key information on the magnetic susceptibility anisotropy. Both experimental and computational approaches have revealed a poor correlation to Bleaney's theory of magnetic anisotropy. CASSCF calculations suggested that the magnetic susceptibility is very sensitive to small geometric variations within the first coordination sphere, whereas DFT analyses indicate that it is the thermal accessibility of low energy vibrational modes that may lead to distortion. Parallel NMRD and EPR studies on the three Gd(iii) complexes revealed good correspondence in estimating the electronic relaxation time. The Gd(iii) tris-pyridinecarboxylate complex possesses a very long electronic relaxation time making it a promising starting point for responsive gadolinium EPR probe design.

Unravelling the Complexities of Pseudocontact Shift Analysis in Lanthanide Coordination Complexes of Differing Symmetry.

In two closely related series of eight-coordinate lanthanide complexes, a switch in the sign of the dominant ligand field parameter and striking variations in the sign, amplitude and orientation of the main component of the magnetic susceptibility tensor as the Ln3+ ion is permuted conspire to mask modest changes in NMR paramagnetic shifts, but are evident in Yb EPR and Eu emission spectra.

Using Redox-Active π Bridging Ligand as a Control Switch of Intramolecular Magnetic Interactions.

Intramolecular magnetic interactions in the dinuclear complexes [(tpy)Ni(tphz)Ni(tpy)] n+ ( n = 4, 3, and 2; tpy, terpyridine; tphz, tetrapyridophenazine) were tailored by changing the oxidation state of the pyrazine-based bridging ligand. While its neutral form mediates a weak antiferromagnetic (AF) coupling between the two S = 1 Ni(II), its reduced form, tphz•-, promotes a remarkably large ferromagnetic exchange of +214(5) K with Ni(II) spins. Reducing twice the bridging ligand affords weak Ni-Ni interactions, in marked contrast to the Co(II) analogue. Those experimental results, supported by a careful examination of the involved orbitals, provide a clear understanding of the factors which govern strength and sign of the magnetic exchange through an aromatic bridging ligand, a prerequisite for the rational design of strongly coupled molecular systems and high TC molecule-based magnets.

Exquisite sensitivity of the ligand field to solvation and donor polarisability in coordinatively saturated lanthanide complexes.

Crystallographic, emission and NMR studies of a series of C3-symmetric, nine-coordinate substituted pyridyl triazacyclononane Yb(iii) and Eu(iii) complexes reveal the impact of local solvation and ligand dipolar polarisability on ligand field strength, leading to dramatic variations in pseudocontact NMR shifts and emission spectral profiles, giving new guidance for responsive NMR and spectral probe design.

Lanthanide-induced relaxation anisotropy.

Lanthanide ions accelerate nuclear spin relaxation by two primary mechanisms: dipolar and Curie. Both are commonly assumed to depend on the length of the lanthanide-nucleus vector, but not on its direction. Here we show experimentally that this is wrong - careful proton relaxation data analysis in a series of isostructural lanthanide complexes (Ln = Tb, Dy, Ho, Er, Tm, Yb) reveals angular dependence in both Curie and dipolar relaxation. The reasons are: (a) that magnetic susceptibility anisotropy can be of the same order of magnitude as the isotropic part (contradicting the unstated assumption in Guéron's theory of the Curie relaxation process), and (b) that zero-field splitting can be much stronger than the electron Zeeman interaction (Bloembergen's original theory of the lanthanide-induced dipolar relaxation process makes the opposite assumption). These factors go beyond the well researched cross-correlation effects; they alter the relaxation theory treatment and make strong angular dependencies appear in the nuclear spin relaxation rates. Those dependencies are impossible to ignore - this is now demonstrated both theoretically and experimentally, and suggests that a major revision is needed of the way lanthanide-induced relaxation data are used in structural biology.

A Redox-Active Bridging Ligand to Promote Spin Delocalization, High-Spin Complexes, and Magnetic Multi-Switchability.

A dinuclear CoII complex, [Co2 (tphz)(tpy)2 ]n+ (n=4, 3 or 2; tphz: tetrapyridophenazine; tpy: terpyridine), has been assembled using the redox-active and strongly complexing tphz bridging ligand. The magnetic properties of this complex can be tuned from spin-crossover with T1/2 ≈470 K for the pristine compound (n=4) to single-molecule magnet with an ST =5/2 spin ground state when once reduced (n=3) to finally a diamagnetic species when twice reduced (n=2). The two successive and reversible reductions are concomitant with an increase of the spin delocalization within the complex, promoting remarkably large magnetic exchange couplings and high-spin species even at room temperature.

Chiral probes for α1-AGP reporting by species-specific induced circularly polarised luminescence.

Luminescence spectroscopy has been used to monitor the selective and reversible binding of pH sensitive, macrocyclic lanthanide complexes, [LnL1], to the serum protein α1-AGP, whose concentration can vary significantly in response to inflammatory processes. On binding α1-AGP, a very strong induced circularly-polarised europium luminescence signal was observed that was of opposite sign for human and bovine variants of α1-AGP - reflecting the differences in the chiral environment of their drug-binding pockets. A mixture of [EuL1] and [TbL1] complexes allowed the ratiometric monitoring of α1-AGP levels in serum. Moreover, competitive displacement of [EuL1] from the protein by certain prescription drugs could be monitored, allowing the determination of drug binding constants. Reversible binding of the sulphonamide arm as a function of pH, led to a change of the coordination environment around the lanthanide ion, from twisted square antiprism (TSAP) to a square antiprismatic geometry (SAP), signalled by emission spectral changes and verified by detailed computations and the fitting of NMR pseudocontact shift data in the sulphonamide bound TSAP structure for the Dy and Eu examples. Such analyses allowed a full definition of the magnetic susceptibility tensor for [DyL1].

Spin-state-correlated optical properties of copper(ii)-nitroxide based molecular magnets.

Molecular magnets based on copper(ii) ions and stable nitroxide radicals exhibit promising switchable behavior triggered by a number of external stimuli; however, their spin-state-correlated optical properties vital for photoinduced switching have not been profoundly investigated to date. Herein, the electronic absorption spectra of single crystals of three representatives of this unique family are studied experimentally and theoretically in the visible and near-IR regions. We established that the color of the complexes is mainly determined by optical properties of the nitroxide radicals, whereas the Cu(hfac)2 fragment contributes to the near-IR range with the intensity smaller by an order of magnitude. The thermochromism of these complexes evident upon thermal spin state switching is mainly caused by a spectral shift of the absorption bands of the nitroxides. The vibrational progression observed in the visible range for single crystals as well as for solutions of pure nitroxides is well reproduced by DFT calculations, where the C-C stretching mode governs the observed progression. The analysis of the spectra of single crystals in the near-IR region reveals changes in the energy and in the intensity of the copper(ii) d-d transitions, which are well reproduced by SOC-NEVPT2 calculations and owe to the flip of the Jahn-Teller axis in the coordination environment of copper. Further strategies for designing bidirectional magnetic photoswitches using these appealing compounds are discussed.

Rationalization of Anomalous Pseudocontact Shifts and Their Solvent Dependence in a Series of C3-Symmetric Lanthanide Complexes.

Bleaney's long-standing theory of magnetic anisotropy has been employed with some success for many decades to explain paramagnetic NMR pseudocontact shifts, and has been the subject of many subsequent approximations. Here, we present a detailed experimental and theoretical investigation accounting for the anomalous solvent dependence of NMR shifts for a series of lanthanide(III) complexes, namely [LnL1] (Ln = Eu, Tb, Dy, Ho, Er, Tm, and Yb; L1: 1,4,7-tris[(6-carboxypyridin-2-yl)methyl]-1,4,7-triazacyclononane), taking into account the effect of subtle ligand flexibility on the electronic structure. We show that the anisotropy of the room temperature magnetic susceptibility tensor, which in turn affects the sign and magnitude of the pseudocontact chemical shift, is extremely sensitive to minimal structural changes in the first coordination sphere of L1. We show that DFT structural optimizations do not give accurate structural models, as assessed by the experimental chemical shifts, and thus we determine a magnetostructural correlation and employ this to evaluate the accurate solution structure for each [LnL1]. This approach allows us to explain the counterintuitive pseudocontact shift behavior, as well as a striking solvent dependence. These results have important consequences for the analysis and design of novel magnetic resonance shift and optical emission probes that are sensitive to the local solution environment and polarity.