Weak Exchange Interactions in Multispin Systems: EPR Studies of Metalloporphyrins Decorated with {Cr7Ni} Rings.

Both metalloporphyrins and heterometallic {Cr7Ni} rings are of significant research interest due to their proposed roles in quantum information processing devices. In this study, we present a series of complexes in which [Cr7NiF3(Etglu)(O2CtBu)15] (N-EtgluH5 = N-ethyl-d-glucamine) heterometallic rings are coordinated to metalloporphyrin linkers: the symmetric [M(TPyP)] for M = Cu2+, VO2+, and H2TPyP = 5,10,15,20-tetra(4-pyridyl)porphyrin; and the asymmetric [{VO}(TrPPyP)] for H2(TrPPyP) = 5,10,15-(triphenyl)-20-(4-pyridyl)porphyrin. The magnetic interactions present in these complexes are unraveled using the continuous wave (CW) electron paramagnetic resonance (EPR) technique. The nature of the coupling between the {Cr7Ni} rings and the central metalloporphyrin is assessed by numerical simulations of CW EPR spectra and determined to be on the order of 0.01 cm-1, larger than the dipolar ones and suitable for individual spin addressability in multiqubit architectures.

Simple and effective in situ sample illumination for electron paramagnetic resonance.

Illumination into an electron paramagnetic resonance (EPR) spectrometer is commonly carried out through the optical window, perpendicular to the sample and magnetic field. Here we show that significant improvements can be obtained by using the walls of the EPR tube as a light guide, with the light scattered only around the sample-containing area.

Determining and controlling conformational information from orientationally selective light-induced triplet-triplet electron resonance spectroscopy for a set of bis-porphyrin rulers.

We recently reported a new technique, light-induced triplet-triplet electron resonance (LITTER) spectroscopy, which allows quantification of the dipolar interaction between the photogenerated triplet states of two chromophores. Here we carry out a systematic LITTER study, considering orientation selection by the detection pulses, of a series of bis-porphyrin model peptides with different porphyrin-porphyrin distances and relative orientations. Orientation-dependent analysis of the dipolar datasets yields conformational information of the molecules in frozen solution which is in good agreement with density functional theory predictions. Additionally, a fast partial orientational-averaging treatment produces distance distributions with minimized orientational artefacts. Finally, by direct comparison of LITTER data to double electron-electron resonance (DEER) measured on a system with Cu(II) coordinated into the porphyrins, we demonstrate the advantages of the LITTER technique over the standard DEER methodology. This is due to the remarkable spectroscopic properties of the photogenerated porphyrin triplet state. This work sets the basis for the use of LITTER in structural investigations of unmodified complex biological macromolecules, which could be combined with Förster resonance energy transfer and microscopy inside cells.

Title: experimental realisation of multi-qubit gates using electron paramagnetic resonance.

Quantum information processing promises to revolutionise computing; quantum algorithms have been discovered that address common tasks significantly more efficiently than their classical counterparts. For a physical system to be a viable quantum computer it must be possible to initialise its quantum state, to realise a set of universal quantum logic gates, including at least one multi-qubit gate, and to make measurements of qubit states. Molecular Electron Spin Qubits (MESQs) have been proposed to fulfil these criteria, as their bottom-up synthesis should facilitate tuning properties as desired and the reproducible production of multi-MESQ structures. Here we explore how to perform a two-qubit entangling gate on a multi-MESQ system, and how to readout the state via quantum state tomography. We propose methods of accomplishing both procedures using multifrequency pulse Electron Paramagnetic Resonance (EPR) and apply them to a model MESQ structure consisting of two nitroxide spin centres. Our results confirm the methodological principles and shed light on the experimental hurdles which must be overcome to realise a demonstration of controlled entanglement on this system.

Direct Comparison between Förster Resonance Energy Transfer and Light-Induced Triplet-Triplet Electron Resonance Spectroscopy.

To carry out reliable and comprehensive structural investigations, the exploitation of different complementary techniques is required. Here, we report that dual triplet-spin/fluorescent labels enable the first parallel distance measurements by electron spin resonance (ESR) and Förster resonance energy transfer (FRET) on exactly the same molecules with orthogonal chromophores, allowing for direct comparison. An improved light-induced triplet-triplet electron resonance method with 2-color excitation is used, improving the signal-to-noise ratio of the data and yielding a distance distribution that provides greater insight than the single distance resulting from FRET.

Hexanuclear Ln6 L6 Complex Formation by Using an Unsymmetric Ligand.

Multinuclear, self-assembled lanthanide complexes present clear opportunities as sensors and imaging agents. Despite the widely acknowledged potential of this class of supramolecule, synthetic and characterization challenges continue to limit systematic studies into their self-assembly restricting the number and variety of lanthanide architectures reported relative to their transition metal counterparts. Here we present the first study evaluating the effect of ligand backbone symmetry on multinuclear lanthanide complex self-assembly. Replacement of a symmetric ethylene linker with an unsymmetric amide at the center of a homoditopic ligand governs formation of an unusual Ln6 L6 complex with coordinatively unsaturated metal centers. The choice of triflate as a counterion, and the effect of ionic radii are shown to be critical for formation of the Ln6 L6 complex. The atypical Ln6 L6 architecture is characterized using a combination of mass spectrometry, luminescence, DOSY NMR and EPR spectroscopy measurements. Luminescence experiments support clear differences between comparable Eu6 L6 and Eu2 L3 complexes, with relatively short luminescent lifetimes and low quantum yields observed for the Eu6 L6 structure indicative of non-radiative decay processes. Synthesis of the Gd6 L6 analogue allows three distinct Gd⋯Gd distance measurements to be extracted using homo-RIDME EPR experiments.

Frequency swept pulses for the enhanced resolution of ENDOR spectra detecting on higher spin transitions of Gd(III).

Half-Integer High Spin (HIHS) systems with zero-field splitting (ZFS) parameters below 1 GHz are generally dominated by the spin |─1/2>→|+1/2 > central transition (CT). Accordingly, most pulsed Electron Paramagnetic Resonance (EPR) experiments are performed at this position for maximum sensitivity. However, in certain cases it can be desirable to detect higher spin transitions away from the CT in such systems. Here, we describe the use of frequency swept Wideband, Uniform Rate, Smooth Truncation (WURST) pulses for transferring spin population from the CT, and other transitions, of Gd(III) to the neighbouring higher spin transition |─3/2>→|─1/2 > at Q- and W-band frequencies. Specifically, we demonstrate this approach to enhance the sensitivity of 1H Mims Electron-Nuclear Double Resonance (ENDOR) measurements on two model Gd(III) aryl substituted 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) complexes, focusing on transitions other than the CT. We show that an enhancement factor greater than 2 is obtained for both complexes at Q- and W-band frequencies by the application of two polarising pulses prior to the ENDOR sequence. This is in agreement with simulations of the spin dynamics of the system during WURST pulse excitation. The technique demonstrated here should allow more sensitive experiments to be measured away from the CT at higher operating temperatures, and be combined with any relevant pulse sequence.

Fullerene Complexation in a Hydrogen-Bonded Porphyrin Receptor via Induced-Fit: Cooperative Action of Tautomerization and C-H···π Interactions.

A supramolecular chiral hydrogen-bonded tetrameric aggregate possessing a large cavity and tetraarylporphyrin substituents was assembled using alternating 4H- and 2H-bonds between ureidopyrimidinone and isocytosine units, respectively. The aggregation mode was rationally shifted from social to narcissistic self-sorting by changing urea substituent size only. The H-bonded tetramer forms a strong complex with C60 guest, at the same time undergoing remarkable structural changes. Namely, the cavity adjusts to the guest via keto-to-enol tautomerization of the ureidopyrimidinone unit and as a result, porphyrin substituents move apart from each other in a scissor blade-like opening fashion. The rearrangement is accompanied by C-H···π interaction between the alkyl solubilizing groups and the nearby placed porphyrin π-systems. The latter interaction was found to be crucial for the guest complexation event, providing energetic compensation for otherwise costly tautomerization. We showed that only the systems possessing sufficiently long alkyl chains capable of interacting with a porphyrin ring are able to form a complex with C60. The structural rearrangement of the tetramer was quantitatively characterized by electron paramagnetic resonance pulsed dipolar spectroscopy measurements using photogenerated triplets of porphyrin and C60 as spin probes. Further exploring the C-H···π interaction as a decisive element for the C60 recognition, we investigated the guest-induced self-sorting phenomenon using scrambled tetramer assemblies composed of two types of monomers possessing alkyl chains of different lengths. The presence of the fullerene guest has enabled the selective scavenging of monomers capable of C-H···π interaction to form homo-tetrameric aggregates.

Magnetic and Electronic Structural Properties of the S3 State of Nature's Water Oxidizing Complex: A Combined Study in ELDOR-Detected Nuclear Magnetic Resonance Spectral Simulation and Broken-Symmetry Density Functional Theory.

ELDOR-detected nuclear magnetic resonance (EDNMR) spectral simulations combined with broken-symmetry density functional theory (BS-DFT) calculations are used to obtain and to assign the 55Mn hyperfine coupling constants (hfcs) for modified forms of the water oxidizing complex in the penultimate S3 state of the water oxidation cycle. The study shows that an open cubane form of the core Mn4CaO6 cluster explains the magnetic properties of the dominant S = 3 species in all cases studied experimentally with no need to invoke a closed cubane intermediate possessing a distorted pentacoordinate Mn4 ion as recently suggested. EDNMR simulations found that both the experimental bandwidth and multinuclear transitions may alter relative EDNMR peak intensities, potentially leading to incorrect assignment of hfcs. The implications of these findings for the water oxidation mechanism are discussed.

Erythrosin B as a New Photoswitchable Spin Label for Light-Induced Pulsed EPR Dipolar Spectroscopy.

We present a new photoswitchable spin label for light-induced pulsed electron paramagnetic resonance dipolar spectroscopy (LiPDS), the photoexcited triplet state of erythrosin B (EB), which is ideal for biological applications. With this label, we perform an in-depth study of the orientational effects in dipolar traces acquired using the refocused laser-induced magnetic dipole technique to obtain information on the distance and relative orientation between the EB and nitroxide labels in a rigid model peptide, in good agreement with density functional theory predictions. Additionally, we show that these orientational effects can be averaged to enable an orientation-independent analysis to determine the distance distribution. Furthermore, we demonstrate the feasibility of these experiments above liquid nitrogen temperatures, removing the need for expensive liquid helium or cryogen-free cryostats. The variety of choices in photoswitchable spin labels and the affordability of the experiments are critical for LiPDS to become a widespread methodology in structural biology.

Modelling Conformational Flexibility in a Spectrally Addressable Molecular Multi-Qubit Model System.

Dipolar coupled multi-spin systems have the potential to be used as molecular qubits. Herein we report the synthesis of a molecular multi-qubit model system with three individually addressable, weakly interacting, spin 1 / 2 ${{ 1/2 }}$ centres of differing g-values. We use pulsed Electron Paramagnetic Resonance (EPR) techniques to characterise and separately address the individual electron spin qubits; CuII , Cr7 Ni ring and a nitroxide, to determine the strength of the inter-qubit dipolar interaction. Orientation selective Relaxation-Induced Dipolar Modulation Enhancement (os-RIDME) detecting across the CuII spectrum revealed a strongly correlated CuII -Cr7 Ni ring relationship; detecting on the nitroxide resonance measured both the nitroxide and CuII or nitroxide and Cr7 Ni ring correlations, with switchability of the interaction based on differing relaxation dynamics, indicating a handle for implementing EPR-based quantum information processing (QIP) algorithms.

Light-induced pulsed dipolar EPR spectroscopy for distance and orientation analysis.

Measuring distances in biology at the molecular level is of great importance for understanding the structure and function of proteins, nucleic acids and other biological molecules and their complexes. Pulsed Dipolar Spectroscopy (PDS) offers advantages with respect to other methods as it is uniquely sensitive and specific to electronic spin centers and allows measurements in near-native conditions, comprising the in-cell environment. PDS methods measure the electron spin-spin dipolar interaction, therefore they require the presence of at least two paramagnetic centers, which are often stable radicals. Recent developments have introduced transient triplet states, photo-activated by a laser pulse, as spin labels and probes, thereby establishing a new family of techniques-Light-induced PDS (LiPDS). In this chapter, an overview of these methods is provided, looking at the chromophores that can be used for LiPDS and some of the technical aspects of the experiments. A guide to the choice of technique that can yield the best results, depending on the type of system studied and the information required, is provided. Examples of previous LiPDS studies of model systems and proteins are given. Characterization data for the chromophores used in these studies is tabulated to help selection of appropriate triplet state probes in future studies.

Real-world clinical and cost-effectiveness of community clozapine initiation: mirror cohort study.

BACKGROUND: Clozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear. AIMS: The aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine. METHOD: This was a naturalistic study of community patients recommended for clozapine treatment. RESULTS: Of 158 patients recommended for clozapine treatment, 88 (56%) patients agreed to clozapine initiation and, of these, 58 (66%) were successfully established on clozapine. The success rate for community initiation was 65.4%; which was not significantly different from that for in-patient initiation (58.82%, χ2(1,88) = 0.47, P = 0.49). Following clozapine initiation, there was a significant reduction in median out-patient visits over 1 year (from 24.00 (interquartile range (IQR) = 14.00-41.00) to 13.00 visits (IQR = 5.00-24.00), P < 0.001), and 2 years (from 47.50 visits (IQR = 24.75-71.00) to 22.00 (IQR = 11.00-42.00), P < 0.001), and a 74.71% decrease in psychiatric hospital bed days (z = -2.50, P = 0.01). Service-use costs decreased (1 year: -£963/patient (P < 0.001); 2 years: -£1598.10/patient (P < 0.001). Subanalyses for community-only initiation also showed significant cost reductions (1 year: -£827.40/patient (P < 0.001); 2 year: -£1668.50/patient (P < 0.001) relative to costs prior to starting clozapine. Relative to before initiation, symptom severity was improved in patients taking clozapine at discharge (median Positive and Negative Syndrome Scale total score: initial visit: 80 (IQR = 71.00-104.00); discharge visit 50.5 (IQR = 44.75-75.00), P < 0.001) and at 2 year follow-up (Health of Nation Outcome Scales total score median initial visit: 13.00 (IQR = 9.00-15.00); 2 year follow-up: 8.00 (IQR = 3.00-13.00), P = 0.023). CONCLUSIONS: These findings indicate that community initiation of clozapine is feasible and is associated with significant reductions in costs, service use and symptom severity.

Lessons for Uptake and Engagement of a Smartphone App (SURE Recovery) for People in Recovery From Alcohol and Other Drug Problems: Interview Study of App Users.

BACKGROUND: Mobile health apps promoting health and well-being have substantial potential but low uptake and engagement. Barriers common to addiction treatment app uptake and engagement include poor access to mobile technology, Wi-Fi, or mobile data, plus low motivation among non-treatment-seeking users to cut down or quit. Working with people who used substances, we had previously designed and published an app to support recovery from alcohol and other drug problems. The app, which is available for free from the Apple App Store and Google Play, is called SURE Recovery. OBJECTIVE: The aim of this paper is to undertake a qualitative study to ascertain end users' views and experiences of the SURE Recovery app, including how it might be improved, and present the findings on uptake and engagement to assist other researchers and app developers working on similar apps for people experiencing alcohol and other drug problems. METHODS: Semistructured telephone interviews were conducted with 20 people (n=12, 60%, men and n=8, 40%, women aged 25-63 years; all identifying as White British) who had varied patterns of using the app. The audio recordings were transcribed, and the data were coded and analyzed through Iterative Categorization. RESULTS: Analyses identified three main factors relevant to uptake (discoverability of the app, personal relevance, and expectations and motivations) and three main factors relevant to engagement (the appeal and relevance of specific features, perceived benefits, and the need for improvements). The findings on uptake and engagement were largely consistent with our own earlier developmental work and with other published literature. However, we additionally found that uptake was strongly affected by first impressions, including trust and personal recommendations; that users were attracted to the app by their need for support and curiosity but had relatively modest expectations; that engagement increased if the app made users feel positive; and that people were unlikely to download, or engage with, the app if they could not relate to, or identify with, aspects of its content. CONCLUSIONS: Incorporating end-user views into app design and having a network of supportive partners (ie, credible organizations and individuals who will champion the app) seem to increase uptake and engagement among people experiencing alcohol and other drug problems. Although better digital literacy and access to devices and mobile data are needed if addiction recovery apps are to reach their full potential, we should not evaluate them based only on observable changes in substance use behaviors. How using an app makes a person feel is more transient and difficult to quantify but also relevant to uptake and engagement.

Solvent-Dependent Reactivity and Photochemistry of Dinuclear and Mononuclear Platinum(IV) Azido Triazaolato Complexes.

Reaction between the platinum(IV) azido complex trans,trans,trans-[Pt(py)2(N3)2(OH)2] (1) and 1,4-diphenyl-2-butyne-1,4-dione 2 in MeCN produces the intermediate peroxide-bridged dimeric platinum(IV) azido triazolato species (5), which has been characterised by X-ray crystallography. However, if the reaction between 1 and 2 is conducted in MeOH it results in decomposition. Over time in MeCN, dimer (5) converts into mononuclear complexes trans,trans,trans-[Pt(py)2(N3)(triazole)(OH)2] (3 a/3 b), which are in dynamic exchange. If resuspended in protic solvents (MeOH,H2O), 3 a/3 b undergo a slow (22 d) irreversible rearrangement to a cyclised platinum(IV) species 4 which contains a formally N,O-chelated ligand. Conversion of 3 a/3 b to 4 in d 4-MeOH can be accelerated (384x) by irradiation with visible light, although continued irradiation also produces N3 . and OH. radicals, and the [4-N3]+ species can be readily detected by ESI-MS. Solvent choice significantly effects both the cycloaddition reaction between 1 and 2, and the stability of the resultant complexes.

Orientation-Selective and Frequency-Correlated Light-Induced Pulsed Dipolar Spectroscopy.

We explore the potential of orientation-resolved pulsed dipolar spectroscopy (PDS) in light-induced versions of the experiment. The use of triplets as spin-active moieties for PDS offers an attractive tool for studying biochemical systems containing optically active cofactors. Cofactors are often rigidly bound within the protein structure, providing an accurate positional marker. The rigidity leads to orientation selection effects in PDS, which can be analyzed to give both distance and mutual orientation information. Herein we present a comprehensive analysis of the orientation selection of a full set of light-induced PDS experiments. We exploit the complementary information provided by the different light-induced techniques to yield atomic-level structural information. For the first time, we measure a 2D frequency-correlated laser-induced magnetic dipolar spectrum, and we are able to monitor the complete orientation dependence of the system in a single experiment. Alternatively, the summed spectrum enables an orientation-independent analysis to determine the distance distribution.

Light-Induced Triplet-Triplet Electron Resonance Spectroscopy.

We present a new technique, light-induced triplet-triplet electron resonance spectroscopy (LITTER), which measures the dipolar interaction between two photoexcited triplet states, enabling both the distance and angular distributions between the two triplet moieties to be determined on a nanometer scale. This is demonstrated for a model bis-porphyrin peptide that renders dipolar traces with strong orientation selection effects. Using simulations and density functional theory calculations, we extract distance distributions and relative orientations of the porphyrin moieties, allowing the dominant conformation of the peptide in a frozen solution to be identified. LITTER removes the requirement of current light-induced electron spin resonance pulse dipolar spectroscopy techniques to have a permanent paramagnetic moiety, becoming more suitable for in-cell applications and facilitating access to distance determination in unmodified macromolecular systems containing photoexcitable moieties. LITTER also has the potential to enable direct comparison with Förster resonance energy transfer and combination with microscopy inside cells.

Conformational Flexibility of Hybrid [3]- and [4]-Rotaxanes.

The synthesis, structures, and properties of [4]- and [3]-rotaxane complexes are reported where [2]-rotaxanes, formed from heterometallic {Cr7Ni} rings, are bound to a fluoride-centered {CrNi2} triangle. The compounds have been characterized by single-crystal X-ray diffraction and have the formulas [CrNi2(F)(O2CtBu)6]{(BH)[Cr7NiF8(O2CtBu)16]}3 (3) and [CrNi2(F)(O2CtBu)6(THF)]{(BH)[Cr7NiF8(O2CtBu)16]}2 (4), where B = py-CH2CH2NHCH2C6H4SCH3. The [4]-rotaxane 3 is an isosceles triangle of three [2]-rotaxanes bound to the central triangle while the [3]-rotaxane 4 contains only two [2]-rotaxanes bound to the central triangle. Studies of the behavior of 3 and 4 in solution by small-angle X-ray scattering and atomistic molecular dynamic simulations show that the structure of 3 is similar to that found in the crystal but that 4 has a different conformation to the crystal. Continuous wave and pulsed electron paramagnetic resonance spectroscopy was used to study the structures present and demonstrate that in frozen solutions (at 5 K) 4 forms more extended molecules than 3 and with a wider range of conformations.

An NMR and MD study of complexes of bacteriophage lambda lysozyme with tetra- and hexa-N-acetylchitohexaose.

The X-ray structure of lysozyme from bacteriophage lambda (λ lysozyme) in complex with the inhibitor hexa-N-acetylchitohexaose (NAG6) (PDB: 3D3D) has been reported previously showing sugar units from two molecules of NAG6 bound in the active site. One NAG6 is bound with four sugar units in the ABCD sites and the other with two sugar units in the E'F' sites potentially representing the cleavage reaction products; each NAG6 cross links two neighboring λ lysozyme molecules. Here we use NMR and MD simulations to study the interaction of λ lysozyme with the inhibitors NAG4 and NAG6 in solution. This allows us to study the interactions within the complex prior to cleavage of the polysaccharide. 1 HN and 15 N chemical shifts of λ lysozyme resonances were followed during NAG4/NAG6 titrations. The chemical shift changes were similar in the two titrations, consistent with sugars binding to the cleft between the upper and lower domains; the NMR data show no evidence for simultaneous binding of a NAG6 to two λ lysozyme molecules. Six 150 ns MD simulations of λ lysozyme in complex with NAG4 or NAG6 were performed starting from different conformations. The simulations with both NAG4 and NAG6 show stable binding of sugars across the D/E active site providing low energy models for the enzyme-inhibitor complexes. The MD simulations identify different binding subsites for the 5th and 6th sugars consistent with the NMR data. The structural information gained from the NMR experiments and MD simulations have been used to model the enzyme-peptidoglycan complex.