Unravelling Guest Dynamics in Crystalline Molecular Organics Using H Solid-State NMR and Molecular Dynamics Simulation.

H solid-state NMR and atomistic molecular dynamics (MD) simulations are used to understand the disorder of guest solvent molecules in two cocrystal solvates of the pharmaceutical furosemide. Traditional approaches to interpreting the NMR data fail to provide a coherent model of molecular behavior and indeed give misleading kinetic data. In contrast, the direct prediction of the NMR properties from MD simulation trajectories allows the NMR data to be correctly interpreted in terms of combined jump-type and libration-type motions.

Thermoelectric Enhancement in Single Organic Radical Molecules.

Organic thermoelectric materials have potential for wearable heating, cooling, and energy generation devices at room temperature. For this to be technologically viable, high-conductance () and high-Seebeck-coefficient () materials are needed. For most semiconductors, the increase in is accompanied by a decrease in .

DEER and RIDME Measurements of the Nitroxide-Spin Labelled Copper-Bound Amine Oxidase Homodimer from Arthrobacter Globiformis.

Unlabelled: In the study of biological structures, pulse dipolar spectroscopy (PDS) is used to elucidate spin-spin distances at nanometre-scale by measuring dipole-dipole interactions between paramagnetic centres. The PDS methods of Double Electron Electron Resonance (DEER) and Relaxation Induced Dipolar Modulation Enhancement (RIDME) are employed, and their results compared, for the measurement of the dipolar coupling between nitroxide spin labels and copper-II (Cu(II)) paramagnetic centres within the copper amine oxidase from (AGAO). The distance distribution results obtained indicate that two distinct distances can be measured, with the longer of these at c.

Regioisomeric Family of Novel Fluorescent Substrates for SHIP2.

SHIP2 (SH2-domain containing inositol 5-phosphatase type 2) is a canonical 5-phosphatase, which, through its catalytic action on PtdInsP, regulates the PI3K/Akt pathway and metabolic action of insulin. It is a drug target, but there is limited evidence of inhibition of SHIP2 by small molecules in the literature. With the goal to investigate inhibition, we report a homologous family of synthetic, chromophoric benzene phosphate substrates of SHIP2 that display the headgroup regiochemical hallmarks of the physiological inositide substrates that have proved difficult to crystallize with 5-phosphatases.

Cobalt-based molecular electrocatalysis of nitrile reduction: evolving sustainability beyond hydrogen.

Two new cobalt bis-iminopyridines, [Co(DDP)(H2O)2](NO3)2 (1, DDP = cis-[1,3-bis(2-pyridinylenamine)] cyclohexane) and [Co(cis-DDOP)(NO3)](NO3) (2, cis-DDOP = cis-3,5-bis[(2-Pyridinyleneamin]-trans-hydroxycyclohexane) electrocatalyse the 4-proton, 4-electron reduction of acetonitrile to ethylamine. For 1, this reduction occurs in preference to reduction of protons to H2. A coordinating hydroxyl proton relay in 2 reduces the yield of ethylamine and biases the catalytic system back towards H2.

Direct Prediction of EPR Spectra from Lipid Bilayers: Understanding Structure and Dynamics in Biological Membranes.

Of the many biophysical techniques now being brought to bear on studies of membranes, electron paramagnetic resonance (EPR) of nitroxide spin probes was the first to provide information about both mobility and ordering in lipid membranes. Here, we report the first prediction of variable temperature EPR spectra of model lipid bilayers in the presence and absence of cholesterol from the results of large scale fully atomistic molecular dynamics (MD) simulations. Three types of structurally different spin probes were employed in order to study different parts of the bilayer.

Antimicrobial action of the cationic peptide, chrysophsin-3: a coarse-grained molecular dynamics study.

Antimicrobial peptides (AMPs) are small cationic proteins that are able to destabilize a lipid bilayer structure through one or more modes of action. In this study, we investigate the processes of peptide aggregation and pore formation in lipid bilayers and vesicles by the highly cationic AMP, Chrysophsin-3 (chrys-3), using coarse-grained molecular dynamics (CG-MD) simulations and potential of mean force calculations. We study long 50 μs simulations of chrys-3 at different concentrations, both at the surface of dipalmitoylphosphatidylcholine (DPPC) and palmitoyloleoylphosphatidylcholine (POPC) bilayers, and also interacting within the interior of the lipid membrane.

Prediction of EPR Spectra of Lyotropic Liquid Crystals using a Combination of Molecular Dynamics Simulations and the Model-Free Approach.

We report the first application of fully atomistic molecular dynamics (MD) simulations to the prediction of the motional electron paramagnetic resonance (EPR) spectra of lyotropic liquid crystals in different aggregation states doped with a paramagnetic spin probe. The purpose of this study is twofold. First, given that EPR spectra are highly sensitive to the motions and order of the spin probes doped within lyotropic aggregates, simulation of EPR line shapes from the results of MD modelling provides an ultimate test bed for the force fields currently employed to model such systems.

Molecular electrometer and binding of cations to phospholipid bilayers.

Despite the vast amount of experimental and theoretical studies on the binding affinity of cations - especially the biologically relevant Na and Ca - for phospholipid bilayers, there is no consensus in the literature. Here we show that by interpreting changes in the choline headgroup order parameters according to the 'molecular electrometer' concept [Seelig et al., Biochemistry, 1987, 26, 7535], one can directly compare the ion binding affinities between simulations and experiments.

A combined EPR and MD simulation study of a nitroxyl spin label with restricted internal mobility sensitive to protein dynamics.

EPR studies combined with fully atomistic Molecular Dynamics (MD) simulations and an MD-EPR simulation method provide evidence for intrinsic low rotameric mobility of a nitroxyl spin label, Rn, compared to the more widely employed label MTSL (R1). Both experimental and modelling results using two structurally different sites of attachment to Myoglobin show that the EPR spectra of Rn are more sensitive to the local protein environment than that of MTSL. This study reveals the potential of using the Rn spin label as a reporter of protein motions.

Nitrosylation of Nitric-Oxide-Sensing Regulatory Proteins Containing [4Fe-4S] Clusters Gives Rise to Multiple Iron-Nitrosyl Complexes.

The reaction of protein-bound iron-sulfur (Fe-S) clusters with nitric oxide (NO) plays key roles in NO-mediated toxicity and signaling. Elucidation of the mechanism of the reaction of NO with DNA regulatory proteins that contain Fe-S clusters has been hampered by a lack of information about the nature of the iron-nitrosyl products formed. Herein, we report nuclear resonance vibrational spectroscopy (NRVS) and density functional theory (DFT) calculations that identify NO reaction products in WhiD and NsrR, regulatory proteins that use a [4Fe-4S] cluster to sense NO.

Muonium Chemistry at Diiron Subsite Analogues of [FeFe]-Hydrogenase.

The chemistry of metal hydrides is implicated in a range of catalytic processes at metal centers. Gaining insight into the formation of such sites by protonation and/or electronation is therefore of significant value in fully exploiting the potential of such systems. Here, we show that the muonium radical (Mu ), used as a low isotopic mass analogue of hydrogen, can be exploited to probe the early stages of hydride formation at metal centers.

Enantiopure Ferrocene-Based Planar-Chiral Iridacycles: Stereospecific Control of Iridium-Centred Chirality.

Reaction of [IrCp*Cl2 ]2 with ferrocenylimines (Fc=NAr, Ar=Ph, p-MeOC6 H4 ) results in ferrocene C-H activation and the diastereoselective synthesis of half-sandwich iridacycles of relative configuration Sp *,RIr *. Extension to (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline gave highly diastereoselective control over the new elements of planar chirality and metal-based pseudo-tetrahedral chirality, to give both neutral and cationic half-sandwich iridacycles of absolute configuration Sc ,Sp ,RIr . Substitution reactions proceed with retention of configuration, with the planar chirality controlling the metal-centred chirality through an iron-iridium interaction in the coordinatively unsaturated cationic intermediate.

EPR detection and characterisation of a paramagnetic Mo(iii) dihydride intermediate involved in electrocatalytic hydrogen evolution.

EPR spectroscopy and theoretical data show that the slow heterogeneous electron-transfer kinetics associated with the reduction of an 18-electron Mo(IV) acetato dihydride are a consequence of an η(2)-η(1) rearrangement of the carboxylate ligand which gives a unique paramagnetic 17-electron Mo(III) dihydride.

Rate of Molecular Transfer of Allyl Alcohol across an AOT Surfactant Layer Using Muon Spin Spectroscopy.

The transfer rate of a probe molecule across the interfacial layer of a water-in-oil (w/o) microemulsion was investigated using a combination of transverse field muon spin rotation (TF-μSR), avoided level crossing muon spin resonance (ALC-μSR), and Monte Carlo simulations. Reverse microemulsions consist of nanometer-sized water droplets dispersed in an apolar solvent separated by a surfactant monolayer. Although the thermodynamic, static model of these systems has been well described, our understanding of their dynamics is currently incomplete.

Exploring structural and electronic effects in three isomers of tris{bis(trifluoromethyl)phenyl}borane: towards the combined electrochemical-frustrated Lewis pair activation of H2.

Three structural isomers of tris{bis(trifluoromethyl)phenyl}borane have been studied as the acidic component of frustrated Lewis pairs. While the 3,5-substituted isomer is already known to heterolytically cleave H2 to generate a bridging-hydride; ortho-substituents in the 2,4- and 2,5-isomers quench such reactivity through electron donation into the vacant boron pz orbital and steric blocking of the boron centre; as shown by electrochemical, structural and computational studies. Electrochemical studies of the corresponding borohydrides identify that the two-electron oxidation of terminal-hydrides occurs at more positive potentials than observed for [HB(C6F5)3](-), while the bridging-hydride oxidizes at a higher potential still, comparable to that of free H2.

An electrochemical study of frustrated Lewis pairs: a metal-free route to hydrogen oxidation.

Frustrated Lewis pairs have found many applications in the heterolytic activation of H2 and subsequent hydrogenation of small molecules through delivery of the resulting proton and hydride equivalents. Herein, we describe how H2 can be preactivated using classical frustrated Lewis pair chemistry and combined with in situ nonaqueous electrochemical oxidation of the resulting borohydride. Our approach allows hydrogen to be cleanly converted into two protons and two electrons in situ, and reduces the potential (the required energetic driving force) for nonaqueous H2 oxidation by 610 mV (117.

Unexpected weak magnetic exchange coupling between haem and non-haem iron in the catalytic site of nitric oxide reductase (NorBC) from Paracoccus denitrificans1.

Bacterial NOR (nitric oxide reductase) is a major source of the powerful greenhouse gas N2O. NorBC from Paracoccus denitrificans is a heterodimeric multi-haem transmembrane complex. The active site, in NorB, comprises high-spin haem b3 in close proximity with non-haem iron, FeB.

Exploring the fate of the tris(pentafluorophenyl)borane radical anion in weakly coordinating solvents.

We report a kinetic and mechanistic study into the one-electron reduction of the archetypal Lewis acid tris(pentafluorophenyl)borane, B(C(6)F(5))(3), in dichloromethane and 1,2-difluorobenzene. Electrochemical experiments, combined with digital simulations, DFT computational studies and multinuclear NMR analysis allow us to obtain thermodynamic, kinetic and mechanistic information relating to the redox activity of B(C(6)F(5))(3). We show that tris(pentafluorophenyl)borane undergoes a quasi-reversible one-electron reduction followed by rapid chemical decomposition of the B(C(6)F(5))(3)˙(-) radical anion intermediate via a solvolytic radical pathway.

Paramagnetic bridging hydrides of relevance to catalytic hydrogen evolution at metallosulfur centers.

Paramagnetic hydrides are likely intermediates in hydrogen-evolving enzymic and molecular systems. Herein we report the first spectroscopic characterization of well-defined paramagnetic bridging hydrides. Time-resolved FTIR spectroelectrochemical experiments on a subsecond time scale revealed that single-electron transfer to the μ-hydride di-iron dithiolate complex 1 generates a 37-electron valence-delocalized species with no gross structural reorganization of the coordination sphere.

Prediction of nitroxide spin label EPR spectra from MD trajectories: application to myoglobin.

We report the prediction of motional EPR spectra of the metalloprotein sperm whale myoglobin spin labelled with nitroxide directly from Molecular Dynamics (MD) simulations at the atomistic scale. We show that an accurate simulation of EPR spectra can be achieved from a single MD trajectory which is in excellent agreement with experiment. Simulations have been carried out using a general method reported previously by us for the simulation of EPR spectra form single dynamical trajectories.

A general approach for prediction of motional EPR spectra from Molecular Dynamics (MD) simulations: application to spin labelled protein.

A general approach for the prediction of EPR spectra directly and completely from single dynamical trajectories generated from Molecular Dynamics (MD) simulations is described. The approach is applicable to an arbitrary system of electron and nuclear spins described by a general form of the spin-Hamiltonian for the entire motional range. It is shown that for a reliable simulation of motional EPR spectra only a single truncated dynamical trajectory generated until the point when correlation functions of rotational dynamics are completely relaxed is required.

Mechanistic insight into the nitrosylation of the [4Fe-4S] cluster of WhiB-like proteins.

The reactivity of protein bound iron-sulfur clusters with nitric oxide (NO) is well documented, but little is known about the actual mechanism of cluster nitrosylation. Here, we report studies of members of the Wbl family of [4Fe-4S] containing proteins, which play key roles in regulating developmental processes in actinomycetes, including Streptomyces and Mycobacteria, and have been shown to be NO responsive. Streptomyces coelicolor WhiD and Mycobacterium tuberculosis WhiB1 react extremely rapidly with NO in a multiphasic reaction involving, remarkably, 8 NO molecules per [4Fe-4S] cluster.