Professor Brendan Howlin

The crystal structure of orthorhombic Bovine Pancreatic Ribonuclease A has been determined to 0.85 Å resolution using low temperature, 100 K, synchrotron X-ray data collected at 16000 keV (λ = 0.77 Å). This is the first ultra-high-resolution structure of a native form of Ribonuclease A to be reported. Refinement carried out with anisotropic displacement parameters, stereochemical restraints, inclusion of H atoms in calculated positions, five SO 4 2 - moieties, eleven ethanol molecules and 293 water molecules, converged with final R values of R1(Free) = 0.129 (4279 reflections) and R1 = 0.112 (85,346 reflections). The refined structure was deposited in the Protein Data Bank as structure 7p4r. Conserved waters, using four high resolution structures, have been investigated. Cluster analysis identified clusters of water molecules that are associated with the active site of Bovine Ribonuclease A. Particular attention has been paid to making detailed comparisons between the present structure and other high quality Bovine Pancreatic Ribonuclease A X-ray crystal structures with special reference to the deposited classic monoclinic structure 3RN3 Howlin et al. (Acta Crystallogr A 45:851–861, 1989). Detailed studies of various aspects of hydrogen bonding and conformation have been carried out with particular reference to active site residues Lys-1, Lys-7, Gln-11, His-12, Lys-41, Asn-44, Thr-45, Lys-66, His-119 and Ser-123. For the two histidine residues in the active site the initial electron density map gives a clear confirmation that the position of His-12 is very similar in the orthorhombic structure to that in 3RN3. In 3RN3 His-119 exhibited poor electron density which was modelled and refined as two distinct sites, A (65%) and B (35%) but with respect to His-119 in the present ultra-high resolution orthorhombic structure there is clear electron density which was modelled and refined as a single conformation distinct from either conformation A or B in 3RN3. Other points of interest include Serine-32 which is disordered at the end of the sidechain in the present orthorhombic form but has been modelled as a single form in 3RN3. Lysine-66: there is density indicating a possible conformation for this residue. However, the density is relatively weak, and the conformation is unclear. Three types of amino acid representation in the ultra-high resolution electron density are examined: (i) sharp with very clearly resolved features, for example Lys-37; (ii) well resolved but clearly divided into two conformations which are well behaved in the refinement, both having high quality geometry, for example Tyr-76; (iii) poor density and difficult or impossible to model, an example is Lys-31 for which density is missing except for Cβ. The side chains of Gln-11, His-12, Lys-41, Thr-45 and His-119 are generally recognised as being closely involved in the enzyme activity. It has also been suggested that Lys-7, Asp-44, Lys-66, Phe-120, Asp-121 and Ser-123 may also have possible roles in this mechanism. A molecular dynamics study on both structures has investigated the conformations of His-119 which was modelled as two conformations in 3RN3 but is observed to have a single clearly defined conformation in the present orthorhombic structure. MD has also been used to investigate Lys-31, Lys-41 and Ser32. The form of the Ribonuclease A enzyme used in both the present study and in 3RN3 (Howlin et al. in Acta Crystallogr A 45:851–861, 1989) includes a sulphate anion which occupies approximately the same location as the PO 4 2 - phosphate group in protein nucleotide complexes (Borkakoti et al. in J Mol Biol 169:743–755, 1983). The present structure contains 5 SO 4 2 - groups SO41151–SO41155 two of which, SO41152 and SO41153 are disordered, SO41152 being in the active site, and 11 EtOH molecules, EOH A 201–EOH A 211 all of which have good geometry. H atoms were built into the EtOH molecules geometrically. Illustrations of these features in the present structure are included here. The sulphates are presumably present in the material purchased for use in the present study. 293 water molecules are included in the present structure compared to 134 in 3RN3 (Howlin et al. in Acta Crystallogr A 45:851–861, 1989).

Ageing is a major risk factor for many conditions including cancer, cardiovascular and neurodegenerative diseases. Pharmaceutical interventions that slow down ageing and delay the onset of age-related diseases are a growing research area. The aim of this study was to build a machine learning model based on the data of the DrugAge database to predict whether a chemical compound will extend the lifespan of Caenorhabditis elegans. Five predictive models were built using the random forest algorithm with molecular fingerprints and/or molecular descriptors as features. The best performing classifier, built using molecular descriptors, achieved an area under the curve (AUC) score of 0.815 for classifying the compounds in the test set. The features of the model were ranked using the Gini importance measure of the random forest algorithm. The top 30 features included descriptors related to atom and bond counts, topological and partial charge properties. The model was applied to predict the class of compounds in an external database, consisting of 1,738 small-molecules. The chemical compounds of the screening database with a predictive probability of ≥ 0.80 for increasing the lifespan of Caenorhabditis elegans were broadly separated into (i) flavonoids, (ii) fatty acids and conjugates, and (iii) organooxygen compounds.

A recyclable mercury (II) selective dimer based on a calix[4]pyrrole derivative has been synthesised and characterised by Mass and FT- IR Spectrometry, Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray (EDX). Information regarding the ability of the dimer to interact with metal cations was obtained from FTIR and SEM-EDX analyses. A striking feature of micrographs of the loaded dimer is the change of morphology with the cation. Based on these results, optimal conditions for removing cations from water were assessed under different experimental conditions. Results obtained demonstrate that the removal process is fast. Capacity values and selectivity factors show that the dimer is selective for Hg(II) in one and in multiple component metal solutions relative to other cations. Single-ion transfer Gibbs energies from water to a solvent containing common functionalities to those of the dimer were used to assess the counter-ion effect on the removal process. Agreement is found between these data and energy calculations derived from Molecular Simulation studies. Studies on polluted water in the presence of normal water components in addition to toxic metal cations are reported. Further experimental work on wastewater from the mining industry is in progress.

The iron complexes found in solutions containing FeCl 3 and 2,3-dihydroxypyridine and 2-mercapto-3-pyridinol have been studied by pH and conductance titrations together with Mössbauer spectroscopy. Some of these complexes are identified as Fe II species not unlike Fe II catechol and Fe II enterobactin complexes. Black precipitates formed in these systems give evidence for the presence of radicals and such radicals are offered as an explanation for the presence of Fe II . It is proposed, in view of the findings of this paper that 2,3-dihydroxypyridine and 2-mercapto-3-pyridinol are unsuitable as analytical agents for iron analysis.

Acid Sensing Ion Channels (ASICs) are one of the most studied channels of the Epithelial Sodium Channel/Degenerin (ENaC/DEG) superfamily. They are responsible for excitatory responses following acidification of the extracellular medium and are involved in several important physiological roles. The ASIC1 subunit can form a functional homotrimeric channel and its structure is currently the most characterised of the whole ENaC/DEG family. Here we computed the free energy profiles for single ion permeation in two different structures of ASIC1 using both Na+ and Cl- as permeating ions. The first structure is the open structure of the channel from the PDB entry 4NTW, and the second structure is the closed structure with the re-entrant loop which contains the highly conserved `HG' motif form PDB entry 6VTK. Both structures show cation selective free energy profiles, however the profiles of the permeating Na+ differ significantly between the two structures. Indeed, whereas there is only a small energetically favorable (-0.5 kcal mol-1) location for Na+ in the open channel (4NTW) near the end of the pore, we observed a clear ion binding site (-7.8 kcal mol-1) located in between the `GAS' belt and the `HG' loop for the channel containing the re-entrant loop (6VTK). Knowing that the `GAS' motif was determined as the selectivity filter, our results support previous observations while addressing the importance of the `HG' motif for the interactions between the pore and the permeating cations.

Computational simulations can be used to save on both time and costs, complementing experimental work and providing further guidance. Immiscible polymer blends induce phase segregation, and in some cases can produce useful multicoat systems. This works uses a range of Molecular Dynamics Simulations methods, including an extended Flory Huggins Interaction Parameter χ to initially probe the interactions and miscibility between ester monomers commonly used in coil coatings. This work indicates that blends with similar backbone structures or " like with like " show increased miscibility and those with different structures lead to a large χ value and immiscibility. Further to this, polyester blends with different backbone structures have then been coarse grained with MARTINI beads and simulations of 10 µs have been run to identify the morphology of the blends at the mesoscopic level. Finally, the melamine crosslinker commonly used in polyester formulations has previously been shown to form agglomerates at higher melamine content, these agglomerates have been shown in atomistic simulations.

Four structurally related ionic liquids (1-ethyl-3-methylimidazolium acetate, 1-ethyl-3-methylimidazolium diethyl phosphate, 1-ethyl-3-methylimidazolium dicyanamide, and 1-ethyl-3-methylimidazolium thiocyanate) are examined for their storage characteristics and its effect on their ability to initiate the cure of epoxy resins. At ambient temperature, epoxy formulations containing 1-ethyl-3-methylimidazolium acetate and 1-ethyl-3-methylimidazolium thiocyanate display marked colour changes to yield dark red samples with greatly increased viscosity after one day; after six days both samples have undergone vitrification. The epoxy formulation containing 1-ethyl-3-methylimidazolium acetate continued to polymerise even at sub-zero temperatures. Storage in dark bottles retarded the reaction during the 30-minute period that the sample is removed from the freezer prior to an aliquot being taken, but once the autocatalytic low temperature reaction has started, the dark glass no longer provides effective protection. Samples of 1-ethyl-3-methylimidazolium dicyanamide/epoxy were also stored and sampled in the same manner, but no differences were exhibited between the samples in clear and dark brown glass bottles. Infrared and nuclear magnetic resonance studies confirmed that the hygroscopic ionic liquids pick up water readily (coordinating to the H atom at the 2-position on the imidazolium ring), but once dried the initiating ability is lost.

A series of copoly(methoxy-thiocyanurate)s is prepared in good yield and purity, and fully characterised. Many of the resulting polymers, formed at room temperature using phase transfer catalysis, can be cast into films with good resilience and thermal stability (some examples suffer practically no mass loss when held isothermally at 190 °C and only display appreciable losses when held continuously at 225 °C). Char yields of 61-64% are achieved in nitrogen depending on backbone structure. Some problems were encountered with solubility, particularly with copolymers, which limited molecular weights analysis, but values of Mn = 7000-10,000 g mol-1 were obtained for the polycyanurate and polythiocyanurate homopolymers. DSC reveals polymerisation exotherms with maxima at 197-207 °C (ΔHp = 39-48 kJ/mol), which are believed to be due to isomerisation of the (activation energies span 172-205 kJ/mol), since X-ray powder diffraction measurements reveal no evidence of crystalline structure in the resulting product.

Mössbauer spectroscopy and solution studies, together with Evans' Method to measure magnetic moments, on the complexes in the Iron(II)/Iron(III) catechol system are reported. A mechanism previously proposed for the reduction of Iron(III) to Iron(II) is modified by consideration of new evidence for the monoprotonation of the monocatecholato acid stable iron complex. The monoprotonated catechol moiety is the electron donor to the coordinated iron(III) and thus protonation of iron-containing hexadentate catecholate siderophores is probably essential for the reduction.

A systematic technique for protein modelling that is applicable to the design of drugs, peptide vaccines and novel proteins is described. Our approach is knowledge‐based, depending on the structures of homologous or analogous proteins and more generally on a relational data base of protein three‐dimensional structures. The procedure simultaneously aligns the known tertiary structures, selects fragments from the structurally conserved regions on the basis of sequence homology, aligns these with the ‘average structure’ or ‘framework’, builds on the loops selected from homologous proteins or a wider database, substitutes sidechains and energy minimises the resultant model. Applications to modelling an homologous structure, tissue plasminogen activator on the basis of another serine proteinase, and to modelling an analogous protein, HIV viral proteinase on the basis of aspartic proteinases, are described. The converse problem of ab initio design is also addressed: this involves the selection of an amino acid sequence to give a particular tertiary structure, in this case a symmetrical domain of two Greek‐key motifs.

In 2-(2′-pyridyl)phenyltellurium(II) bromide ( 1) the coordination about tellurium may be described as pseudo-trigonal bipyramidal wth bromine (TeBr = 2.707(11) Å) and nitrogen (TeN) = 2.236(11) Å) atoms occupying axial positions. The equatorial plane comprises a carbon atome (TeC = 2.111(6) Å) and two lone pairs of electrons. There are no significant intermolecular interactions between the six independent molecules in the unit cell. Bis[2-2′-pyridyl)phenyltellurium(II) chloride]· p-ethoxy-phenylmercury(II) chloride ( 2) may be regarded as an “inclusion compound” obtained by replacement of two RTeX (X = Cl or Br) molecules by two p-ethoxyphenylmercury(II) chloride entities. There is approximately linear coordination about mercury (CHgCl = 179.2°(4), Hg-C = 2.044(14) and HgCl = 2.328(4) Å) and 2-(2′-pyridyl)phenyltellurium(II) chloride, with a structure similar to that of ( 1) above (TeN = 2.2366(6), TeCl = 2.558(1), TeC = 2.080(25) Å). There are no significant intermolecular contacts.

Wet processes of phosphoric acids produce untreated wastewater containing large amounts of fluoride leading to serious environmental problems. This paper reports fundamental studies on two lower rim functionalised calix[4]arene based receptors namely 5, 11, 17, 23 tetra-tert-butyl, 25, 27 bis [diethylphenylurea]ethoxy, 26, 28 dihydroxycalix[4]arene, 1 and 25, 27 bis[diethylphenylurea]ethoxy, 26, 28 dihydroxycalix[4]arene, 2 and their ionic interactions. It is shown that these receptors only interact with fluoride and phosphate in acetonitrile. Their receptive properties are higher for phosphate (2:1 anion:receptor complex) relative to fluoride (1:1 complex).However thermodynamics shows that these receptors are more selective for fluoride relative to phosphate in the formation of the 1:1 complex. The pathway from fundamental studies to the use of these receptors for removing these anions from water has been tested. The receptive properties of 1 for phosphate are held when the extraction involves aqueous solutions containing individual ions. However in mixtures containing both anions, the kinetics of the process and the selectivity of 1 for fluoride predominate and as a result, fluoride is better extracted than phosphate. The counter-ion effect on the removal process is assessed from Molecular Simulation studies. The removal of fluoride from phosphate is discussed taking into account existing technologies.

The mechanism of reaction between 1-ethyl-3-methylimidazolium acetate and the difunctional diglycidyl ether of bisphenol A (DGEBA) is explored using thermal and spectroscopic methods. Investigation of the 1,3-dialkylimidazolium based ionic liquids comprising the common cation (1-ethyl-3-methylimidazolium) and different anions (acetate, diethyl phosphate, dicyanamide or thiocyanate) via thermogravimetric analysis revealed 1-ethyl-3-methylimidazolium acetate to be the least thermally stable, both in air and nitrogen, and 1-ethyl-3-methylimidazolium dicyanamide to be the most thermally stable. Dynamic differential scanning calorimetry reveals the formulations comprising DGEBA and ionic liquid where it was revealed that the lowest and highest temperature for the onset of reaction were observed for formulations with 1-ethyl-3-methylimidazolium acetate and 1-ethyl-3-methylimidazolium dicyanamide respectively. 1-Ethyl-3-methylimidazolium acetate was shown, via nuclear magnetic resonance (NMR) spectroscopy and residual gas analysis, to degrade at 150 °C to yield dealkylated products including methyl acetate and ethyl acetate as well as 1-methylimidazole and 1- ethylimidazole. The dealkylated imidazole ring is proposed as a route for initiation of the epoxy ring. Adduct formation between 1-ethyl-3-methylimidazoloium acetate and benzaldehyde at room temperature was observed leading to the proposal of the generation of a carbene species as a route for initiation of the epoxy ring in formulations with the acetate anion. NMR analysis of formulations comprising 1-ethyl-3-methylimidazolium thiocyanate and epoxy are believed, at room temperature, to initiate via reaction of the thiocyanate anion with the epoxy ring.At elevated temperatures, it is proposed that a second, competing reaction, involving deprotonation of the imidazolium ring, also becomes active. The three proposed reaction pathways, namely the carbene route, the imidazole route and the counter-ion route, are all proposed to occur when an ionic liquid is used to initiate an epoxy resin.

The thermal decomposition of polyphenolic resins was studied by reactive molecular dynamics (RMD) simulation at elevated temperatures. Atomistic models of the polyphenolic resins to be used in the RMD were constructed using an automatic method which calls routines from the software package Materials Studio. In order to validate the models, simulated densities and heat capacities were compared with experimental values. The most suitable combination of force field and thermostat for this system was the Forcite force field with the Nosé–Hoover thermostat, which gave values of heat capacity closest to those of the experimental values. Simulated densities approached a final density of 1.05–1.08 g/cm3 which compared favorably with the experimental values of 1.16–1.21 g/cm3 for phenol-formaldehyde resins. The RMD calculations were run using LAMMPS software at temperatures of 1250 K and 3000 K using the ReaxFF force field and employing an in-house routine for removal of products of condensation. The species produced during RMD correlated with those found experimentally for polyphenolic systems and rearrangements to form cyclopropane moieties were observed. At the end of the RMD simulations a glassy carbon char resulted.

This study uses the Molecular Operating Environment software (MOE) to generate models to calculate the char yield of polybenzoxazines (PBz). A series of benzoxazine (Bz) monomers were constructed to which a variety of parameters relating to the structure (e.g., water accessible surface, negative van der Waals surface area and hydrophobic volume, etc.) were obtained and a quantitative structure property relationships (QSPR) model was generated. The model was used to generate data for new Bz monomers with desired properties and a comparison was made of predictions based on the QSPR model with the experimental data. This study shows the quality of predictive models and confirms how useful computational screening is prior to synthesis.

Modification of polymer properties by blending is a common practice in the polymer industry. We report here a study of blends of cyanurate polymers by molecular modelling that shows that the final experimentally determined properties can be predicted from first principles modelling to a good degree of accuracy. There is always a compromise between simulation length, accuracy and speed of prediction. A comparison of simulation times shows that 125ps of molecular dynamics simulation at each temperature provides the optimum compromise for models of this size with current technology. This study opens up the possibility of computer aided design of polymer blends with desired physical and mechanical properties.

A series of adducts were prepared based on the reaction of 1-ethyl-3-methylimidazolium acetate and benzal- dehyde in various stoichiometries (from equimolar reaction to benzaldehyde in 10-fold excess) and the resulting adducts were characterized using nuclear magnetic resonance spectroscopy (¹H, ¹³C, DEPT, and HQSC experi- ments). Differential scanning calorimetry was used to examine the initiating behaviour of the adducts towards mono- and di-functional epoxy resins and the data were used to determine kinetic parameters for the poly- merization. The lower temperature peak, due to carbene formation, is sensitive to adduct concentration; the residual ionic liquid in the adduct mixture contributes towards the initiation of the curing reaction. When a monofunctional epoxy and the 1:1 adduct was subjected to a 2-week period of storage at room temperature and sub-zero temperatures in the freezer, the profiles of the thermograms for the frozen samples do not change considerably over the storage period and the formulation retains a light yellow colour (rather than the viscous, dark red appearance of the formulation stored at room temperature).

A series of bis-benzoxazines, prepared in high yield and purity using two synthetic procedures, is reported. Differential scanning calorimetry reveals similar temperatures for the onset of polymerisation (162-180 °C); the higher values representing monomers containing polar bridges or rigid backbones. Dynamic viscoelasticity data reveal glass transition temperatures for the polybenzoxazines ranging from 187 °C to 235 °C; a fluorinated polybenzoxazine consistently yields the highest T of the polymers studied. The latter is interesting since it is superior to many commercial benzoxazines with a relatively high T (235 °C), flexural modulus (5.0 GPa) and flexural strength (146.7 MPa), but coupled with a breaking strain (3.06%) that is uncharacteristically high for polybenzoxazines. The incorporation of fluorine results in a low dielectric loss properties (D = 3.71-4.12 at 10 MHz, D = 0.0109 - 0.0980 at 10 MHz), which are comparable with commercial polybenzoxazines, FR4 and aerospace epoxy resins and superior to commercial bismaleimides.

Updated models of the Rat Cytochrome P450 2D enzymes are produced based on the recent x-ray structures of the Human P450 2D6 enzyme both with and without a ligand bound. The differences in species selectivity between the epimers quinine and quinidine are rationalised using these models and the results are discussed with regard to previous studies. A close approach to the heme is not observed in this study. The x-ray structure of the enzyme with a ligand bound is shown to be a better model for explaining the observed experimental binding of quinine and quinidine. Hence models with larger closed binding sites are recommended for comparative docking studies. This is consistent with molecular recognition in Cytochrome P450 enzymes being the result of a number of non-specific interactions in a large binding site.

The use of molecular simulation techniques in connection with structural polymers is now becoming more widely accepted and is employed as a legitimate way to not only visualize complex structures, but also to replicate empirically determined parameters. In this chapter, the authors present the state-of-the-art uses of molecular simulation (molecular mechanics and molecular dynamics) based on some 24 years of practical experience in the field.

Three cyanate ester monomer or oligomer species: 2,2-bis(4-cyanatophenyl) propane 1, 1-1-bis(4-dicyanatophenyl)ethane 2, and the oligomeric phenolic cyanate (Primaset™ PT30) 3, are blended in various ratios to form binary mixtures, formulated with copper(II) acetylacetonate (200 ppm) in dodecylphenol (1% w/v active copper suspension) and cured (2 K/min to 150 °C + 1 h; 2 K/min to 200 °C + 3 h) followed by a post cure (2 K/min to 260 °C + 1 h). Thermal analysis using DSC reveals good agreement with literature data for the homopolymers: typical polymerisation enthalpies of ca. 97-98 kJ/mol. cyanate are obtained for 1 and 2, with slightly lower values (ca. 80-90 kJ/mol.) obtained for Primaset™ PT30. DMTA data show the possibility of using binary blends of the polymers to yield novel materials with similar thermal and mechanical properties to Primaset™ PT30, while improving the processability of the more highly aromatic oligomer. Two of the homopolymers (1 and 2) and a binary (1:1) blend of the same were simulated. Molecular dynamics experiments reveal good agreement with empirical data generated using DSC, DMTA and TGA. © 2012 Elsevier Ltd. All rights reserved.

In order to understand the structural basis of the observed properties of benzoxazine materials, the technique of quantitative structure-property relationships can be applied to sets of monomers or polymers and the understanding gained can then be used to design new monomers or polymers with the desired properties. In the chapter, this technique is applied to some datasets to predict char yield and glass transition temperature, and to illustrate that, despite the limited nature of the datasets currently available, useful predictions can be made.

The aim of this chapter is to introduce the reader to the practical applications of modern molecular simulation techniques with literature examples drawn specifically from the field of polybenzoxazine research. The increases in computational power ensure that it is possible to apply molecular mechanics and molecular dynamics techniques to the visualisation and simulation of comparatively large model structures comprising in some cases more than six thousand atoms (constructed from a repeat unit containing ca. 250 atoms). This, in turn, offers the potential to replicate a variety of physical and mechanical characteristics with a high degree of accuracy and precision. However, the apparent ease with which modelling may be carried out using modern software is beguiling; the need to validate simulations with real, empirical data is essential to ensure that the researcher obtains meaningful results.

The Molecular Operating Environment software (MOE) is used to construct a series of benzoxazine monomers for which a variety of parameters relating to the structures (e.g. water accessible surface area, negative van der Waals surface area, hydrophobic volume and the sum of atomic polarizabilities, etc.) are obtained and quantitative structure property relationships (QSPR) models are formulated. Three QSPR models (formulated using up to 5 descriptors) are first used to make predictions for the initiator data set (n = 9) and compared to published thermal data; in all of the QSPR models there is a high level of agreement between the actual data and the predicted data (within 0.63-1.86 K of the entire dataset). The water accessible surface area is found to be the most important descriptor in the prediction of T(g). Molecular modelling simulations of the benzoxazine polymer (minus initiator) carried out at the same time using the Materials Studio software suite provide an independent prediction of T(g). Predicted T(g) values from molecular modelling fall in the middle of the range of the experimentally determined T(g) values, indicating that the structure of the network is influenced by the nature of the initiator used. Hence both techniques can provide predictions of glass transition temperatures and provide complementary data for polymer design.

Molecular simulation is becoming an important tool for both understanding polymeric structures and predicting their physical and mechanical properties. In this study, temperature ramped molecular dynamics simulations are used to predict two physical properties (i.e., glass transition temperature and thermal degradation temperature) of a previously synthesised and published telechelic benzoxazine. Plots of simulated density versus temperature show decreases in density within the same temperature range as experimental values for the thermal degradation. The predicted value for the thermal degradation temperature for the cured polybenzoxazine based on the telechelic polyetherketone (PEK) monomer was ca. 400°C, in line with the experimental thermal degradation temperature range of 450°C to 500°C. Mechanical Properties of both the unmodified PEK and the telechelic benzoxazines are simulated and compared to experimental values (where available). The introduction of the benoxazine moieties are predicted to increase the elastic moduli in line with the increase of crosslinking in the system.

Despite their inability to model bond breaking molecular dynamics simulations are shown to predict thermal degradation temperatures of polycyanurate (cyanate ester) homopolymers and nanocomposites in very close agreement with experimental data. Simulated polymer density, used to predict T also shows a reduction within the same temperature range as experimental values for the thermal degradation. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Phagocyte superoxide production by a multicomponent NADPH oxidase is important in host defense against microbial invasion. However inappropriate NADPH oxidase activation causes inflammation. Endothelial cells express NADPH oxidase and endothelial oxidative stress due to prolonged NADPH oxidase activation predisposes many diseases. Discovering the mechanism of NADPH oxidase activation is essential for developing novel treatment of these diseases. The p47(phox) is a key regulatory subunit of NADPH oxidase; however, due to the lack of full protein structural information, the mechanistic insight of p47(phox) phosphorylation in NADPH oxidase activation remains incomplete. Based on crystal structures of three functional domains, we generated a computational structural model of the full p47(phox) protein. Using a combination of in silico phosphorylation, molecular dynamics simulation and protein/protein docking, we discovered that the C-terminal tail of p47(phox) is critical for stabilizing its autoinhibited structure. Ser-379 phosphorylation disrupts H-bonds that link the C-terminal tail to the autoinhibitory region (AIR) and the tandem Src homology 3 (SH3) domains, allowing the AIR to undergo phosphorylation to expose the SH3 pocket for p22(phox) binding. These findings were confirmed by site-directed mutagenesis and gene transfection of p47(phox-/-) coronary microvascular cells. Compared with wild-type p47(phox) cDNA transfected cells, the single mutation of S379A completely blocked p47(phox) membrane translocation, binding to p22(phox) and endothelial O2 (⨪) production in response to acute stimulation of PKC. p47(phox) C-terminal tail plays a key role in stabilizing intramolecular interactions at rest. Ser-379 phosphorylation is a molecular switch which initiates p47(phox) conformational changes and NADPH oxidase-dependent superoxide production by cells.

The miscibility of the dicyanate of bisphenol A, with three dicyanate monomers, with aryl/alkylene ether backbones is studied at different compositions of a binary blend. Solubility parameters are calculated for dicyanate monomers and selected oligomers using the methods of Small and Fedors to predict compatibility. The results are evaluated in terms of the accuracy of the model in reproducing observed data. Gibbs free energy of mixing (ΔGmix) values for selected blends are calculated using the BLENDS module of Cerius2. Empirical data (HPLC and MS) are used to inform the construction of selected models to represent different stages of polymer conversion. DMTA analysis is performed to examine the thermo-mechanical properties of the resulting blends and compared with the simulated blend data.

The reaction of phenyl glycidyl ether (PGE) with 1-ethyl-3-methylimidazolium acetate and 1-ethyl-3-methylimidazolium thiocyanate to initiate the polyetherification reaction was examined using thermal and spectral analysis techniques. The influence of the nucleophilicity of the anions on the deprotonation of the 1-ethyl-3-methylimidazolium cation determined the reaction pathway. The thermal degradation of the ionic liquid liberated the acetate ion and led, subsequently, to the deprotonation of the acidic proton in the imidazole ring. Thus, polymerisation of PGE occurred via a carbene intermediate. The more nucleophilic thiocyanate anion was not sufficiently basic to deprotonate the 1-ethyl-3-methylimidazolium cation, and thus proceeded through direct reaction with the PGE, unless the temperature was elevated and a competing carbene mechanism ensued.

A commercial diglycidyl ether of bisphenol A monomer (Baxxores™ ER 2200, eew 182 g/mole, DGEBA) is thermally polymerized in the presence of an ionic liquid, 1-ethyl-3-methylimidazolium acetate at a variety of loadings (5–45 wt %). The loss modulus data for cured samples, containing 5 wt % initiator, display at least two thermal transitions and the highest storage modulus occurs in the sample that has been cured for the shortest time at the lowest temperature. Samples that are exposed to higher temperatures (140, 150 °C) yield more heterogenous networks, whereas following exposure to a much shorter/lower temperature cure schedule (80 °C) exhibits a considerably higher damping ability than the other samples, coupled with a lower glass transition temperature. Differential scanning calorimetry reveals that the latter sample achieves a conversion of 95%, while crosslink densities for the DGEBA samples containing 5 wt % and 15 wt % are respectively 9.5 × 10-3 mol. dm-3 and 1.2 × 10-3 mol. dm-3 (when cured to 80 °C) and 2.0 × 10-2 mol. dm-3 and 2.4 × 10-3 mol. dm-3 (when cured to 140 °C).

A series of commercial difunctional benzoxazine monomers are characterised carefully using thermal and thermo-mechanical techniques before constructing representative polymer networks using molecular simulation techniques. Good agreement is obtained between replicate analyses and for the kinetic parameters obtained from differential scanning calorimetry data (and determined using the methods of Kissinger and Ozawa). Activation energies range from 85-108 kJ/mol (Kissinger) and 89-110 kJ/mol (Ozawa) for the uncatalysed thermal polymerisation reactions, which achieve conversions of 85-97 %. Glass transition temperatures determined from differential scanning calorimetry and dynamic mechanical thermal analysis are coomparable, ranging from BA-a (151 °C, crosslink density 3.6 x 10-3 mol cm-3) containing the bisphenol A moiety to BP-a, based on a phenolphthalein bridge (239-256 °C, crosslink density 5.5-18.4 x 10-3 mol cm-3, depending on formulation). Molecular dynamics simulations of the polybenzoxazines generally agree well with empirical data, indicating that representative networks have been modelled.

The preparation of a series of oligomeric engineering thermoplastics (PS, PES, PEI and PAI) is reported. H and C NMR and FT-IR/ATR spectroscopic techniques are combined to determine the chemical structure of the synthetic polymers, which are produced in good yield and purity. GPC measurements show the weight average molecular weight (M ) of the synthesised thermoplastics fall in the range 5454-33,866 g mol and display polydispersity indices in the range 1.33-1.82. Glass transition temperatures (T) values measured by DSC, occur between 107 and 257 °C and fall in the pattern PS < PES < PEI < PAI. Molecular simulation is used to probe the structure property relationships displayed by PS and PES and reproduces the elastic properties of PS well within the range of the literature; while the values of PES are less well reproduced. The simulated T values of both oligomers agree well with those obtained empirically using DSC. © 2014 Elsevier Ltd. All rights reserved.

For the first time we present nanoindentation analysis of charred, cured aromatic cyanate esters, which exhibit outstanding mechanical properties when analysed under applied loads of 0.1–300 mN. Following charring (900 C for 10 minutes to achieve graphitised structures), the samples display a remarkable combination of a modulus of elasticity of around 25 GPa and nanohardness of 300 kgf mm2, making them some 30–40% stiffer than bone and practically as hard as tooth enamel. At the same time we find that under the same conditions the chars are highly resilient, displaying complete elastic recovery with very little plastic deformation. When cured in the presence of copper(II) acetylacetonate (200 ppm) in dodecylphenol (1% w/v active copper suspension) to form a polycyanurate, compound (2) forms a dense, consolidated structure compared with compound (1) under the same conditions. At high magnification, the presence of a nanoscale, fibrillar structure is observed, accounting for the high resilience.

A series of reactive blends, comprising a commercial benzoxazine monomer, 2,2-bis(3,4-dihydro-3-phenyl-2H-1,3-benzoxazine)propane, and bisphenol A is prepared and characterized. Thermal analysis and dynamic rheology reveal how the introduction of up to 15 wt % bisphenol A lead to a significant increase in reactivity (the exothermic peak maximum of thermal polymerization is reduced from 245 °C to 215 °C), with a small penalty in glass transition temperature (reduction of 15 K), but similar thermal stability (onset of degradation = 283 °C, char yield = 26%). With higher concentrations of bisphenol A (e.g. 25 wt %), a significantly more reactive blend is produced (exothermic peak maximum = 192 °C), but with a significantly lower thermal stability (onset of degradation = 265 °C, char yield = 22%) and glass transition temperature (128 °C). Attempts to produce a cured plaque containing 35 wt % bisphenol A were unsuccessful, due to brittleness. Molecular modelling is used to replicate successfully the glass transition temperatures (measured using thermal analysis) of a range of copolymers.

Three bis-benzoxazine monomers based on the aniline derivatives of bisphenol A (BA-a), bisphenol F (BF-a), and 3,3'-thiodiphenol (BT-a) are examined using a variety of spectroscopic, chromatographic, and thermomechanical techniques. The effect on the polymerization of the monomers is compared using two common compounds, 3,3'-thiodiphenol (TDP) and 3,3'-thiodipropionic acid (TDA), at a variety of loadings. It is found that the diacid has a greater effect on reducing the onset of polymerization and increasing cross-link density and T g for a given benzoxazine. However, the addition of >5 wt % of the diacid had a detrimental effect on the cross-link density, T g, and thermal stability of the polymer. The kinetics of the polymerization of BA-a were found to be well described using an autocatalytic model for which values of n = 1.64 and m = 2.31 were obtained for the early and later stages of reaction (activation energy = 81 kJ/mol). Following recrystallization the same monomer yielded values n = 1.89, m = 0.89, and E a = 94 kJ/mol (confirming the influence of higher oligomers on reactivity). The choice of additive (in particular the magnitude of its pK a) appears to influence the nature of the network formation from a linear toward a more clusterlike growth mechanism.

A new partially substituted calix[4] pyrrole derivative obtained by the introduction of three thioamide functionalities in the N-rim has been synthesised and fully characterised by 1H,13C, HSQC, ROESY NMR and mass spectroscopy. Computer modelling suggested an alternate conformation which was confirmed through ROESY 1H NMR. The receptor interacts only with the silver cation as shown by 1H NMR. The strength of interaction is quantitatively assessed by titration calorimetry. N-rim modification eliminates the possibility of interaction with anions. Unlike calix[4] pyrrole derivatives obtained by the introduction of functionalities through the meso-position, addition of Hg(NO3)2 leads to the degeneration of the receptor as demonstrated by 1H NMR, FTIR and XPS analyses. This is for the first time reported. Molecular simulation studies show significant strain in the mercury bound ligand in bonds, angles, torsions leading to the destruction of the receptor. Given the negative environmental impact produced by the availability of silver ions in aquatic organisms, the fundamental studies indicate that this receptor offers potential applications for monitoring silver (ion selective electrode) or indeed as a decontaminating material for removing silver ions from water.

Medicinal chemistry has in the past been dominated by learned insights from experienced organic chemists. However, with the advent of computer based methods, computer aided drug design has become prominent. We have compared here the ability of locally sourced expert medicinal chemists to purely automated methods and found that the automated method produces a better potential candidate drug than the expert input. The example chosen is based on inhibitors to Abl-kinase and the successful anti-leukaemic drug imatinib. The proposed molecule is a simple modification of nilotinib and has a docking energy of 4.2 kJ/mol better than the best intuitive molecule.

Molecular simulation is used to probe the structure property relationships displayed by polysulphone (PS) and polyethersulphone (PES) and reproduces closely the temperatures at which thermal degradation occurs (and the glass transition temperatures). Both data sets agree well with those obtained empirically using TGA. The examination of the thermal and thermo-oxidative stability of thermoplastic oligomers (M = 5454-33,866 g mol , PDI 1.33-1.82) based on PS, PES, polyetherimide (PEI) and poly(amide-imide) (PAI), is reported. TGA reveals the least thermally stable polymer is PES (T = ∼250 °C), while PAI (T = ∼350 °C) is the highest: the materials usually display two-step decomposition patterns: scission of bridging group and degradation of backbone structure. A possible mechanism for the degradation of a PAI is proposed on the basis of the empirical and simulation data. This work provides a general method for the prediction of the thermal stability of oligomeric modifiers (and high molecular weight polymers). © 2013 Elsevier Ltd. All rights reserved.

Molecular Operating Environment (MOE) software has great potential when combined with the Quantitative Structure-Property Relationship (QSPR) approach, and was proven to be useful to make good prediction models for series of polybenzoxazines [1–3]. However, the effect of heterogeneities in the crosslinked network to the prediction accuracy is yet to be tested. It was found that polybenzoxazines with polymerisable functional group (e.g. acetylene-based benzoxazines) form up to 40% higher char yield compared to their analogue polybenzoxazines due to the contribution of the polymerisable functional group (e.g. ethynyl triple bond) in the cross-linked network. In order to investigate the effect of the inconsistent cross-linking network, a data set consisting of thirty-three benzoxazines containing various structures of benzoxazines was subdivided into two smaller data sets based on their functional group, either benzoxazines with polymerisable functional group (acetylene-based benzoxazines set (Ace-M)) or non-polymerisable functional group (aniline-based benzoxazines (Ani-M)). Char yield predictions for the polybenzoxazines for these data sets (Ace-M and Ani-M) were compared with the larger thirty-three polybenzoxazines data set (GM) to investigate the effect of the inconsistency in crosslink network on the quality of prediction afforded by the model. Prediction performed by Ace-M and Ani-M were found to be more accurate when compared with the GM with total prediction error of 3.15% from both models compared to the GM (4.81%). Ace-M and Ani-M are each better at predicting the char yields of similar polybenzoxazines (i.e. one model is specific for a polymerisable functional group; the other for non-polymerisable functional group), but GM is more practical as it has greater ‘general’ utility and is applicable to numerous structures. The error shown by GM is considerably small and therefore it is still a good option for prediction and should not be underestimated.

The synthesis and characterisation of a partially substituted calix[4]arene, namely, 5,11,17,23- tetra-tert-butyl,25,27-bis[aminoethoxy] 26,28-dihydroxycalix[4]arene are reported. Its interaction with commonly used pharmaceuticals (clofibric acid, diclofenac and aspirin) was investigated by spectroscopic (1 H NMR and UV), electrochemical (conductance measurements) and thermal (titration calorimetry) techniques. It is concluded on the basis of the experimental work and molecular simulation studies that the receptor interacts selectively with these drugs. Preliminary studies on the selective extraction of these pharmaceuticals from water by the calix receptor are reported and the potential for a carrier mediated sensor based on this ligand for ‘on site’ monitoring of pharmaceuticals is discussed.

Two series of terpoly(methoxy-cyanurate-thiocyanurate)s based on thiodiphenol and dithiodiphenyl sulphide, and dihydroxydiphenylether and dithiodiphenyl ether, are prepared in good yield and purity, and fully characterised. Most of the resulting polymers, formed at room temperature using phase transfer catalysis, can be cast into films with good resilience and thermal stability. Two series of terpoly(methoxy-cyanurate-thiocyanurate)s based on thiodiphenol and dithiodiphenyl sulfide and on dihydroxydiphenyl ether and dithiodiphenyl ether, were prepared in good yield and purity and fully characterized. Most of the resulting polymers, formed at room temperature using phase transfer catalysis, can be cast into films with good resilience and thermal stability (some examples suffer practically no mass loss when held isothermally at 190 °C and only display appreciable losses when held continuously at 225 °C). Char yields of 53%-61% are achieved in nitrogen depending on backbone structure. Some problems were encountered with solubility, particularly with copolymers, which limited molecular weight analysis, but values of Mn = 8000-13000 g mol-1 were obtained for the polymers based on thiodiphenol and dithiodiphenyl sulfide, and Mn = 5000-13000 g mol-1 for the polymers based on dihydroxydiphenyl ether and dithiodiphenyl ether. DSC reveals polymerization exotherms with maxima at 184-207 °C (ΔHp = 43-59 kJ mol-1), which are believed to be due to isomerization of the cyanurate to the isocyanurate (activation energies span 159-195 kJ mol-1). Molecular simulation shows that diphenylether and diphenylsulfide display very similar conformational energy surfaces and would therefore be expected to adopt similar conformations, but the diphenylsulfide offers less resistance to deformations that increase the proximity of the two phenyl rings and results in more resilient films. © 2013 Society of Chemical Industry.

The effect of heating rate (2, 8 and 15 K min-1) during the initial stages of cure of 2,2-bis(3,4-dihydro-3- phenyl-2H-1,3-benzoxazine)propane is examined. The rate of heating has a marked effect on the observed modulus, measured by DMTA, with the higher heating rate giving rise to an increase in storage modulus of ca. 1000 MPa, although this is not accompanied by an increase in glass transition temperature. The thermal stability of the resulting polybenzoxazines also differs with the slower heating rate giving rise to less thermally stable structures. Data obtained from Raman spectroscopy (when combined with principal components analysis) suggest subtle changes in the mechanism during the early stages of reaction associated C–N–C and C–O moieties, some of which persist following a higher temperature postcure step leading to a crosslinked network with higher aliphatic character.

Three cyanate ester monomer or oligomer species: 2,2-bis(4-cyanatophenyl)propane 1, 1-1-bis(4-cyanatophenyl)ethane (2), and the oligomeric phenolic cyanate (PrimasetTM PT30) (3), are blended in various ratios with bis(4-maleimidophenyl)methane, (4), to form binary and ternary mixtures (11 in total) and cured, in the absence of catalysts (3 K/min to 150 °C + 1 hour; 3 K/min to 200 °C + 3 hours), followed by a post cure (3 K/min to 260 °C + 1 hour). The use of liquid monomer, (2), offers the possibility of liquid processing in blends containing minority compositions of bismaleimide. Glycidylmethacrylate is explored as a reactive diluent (2.5-10 wt %) to linked interpenetrating network polymer structures comprising cyanate ester and bismaleimide components with glass transition temperatures of 267-275 ºC, depending on composition; the onset of thermo-oxidative degradation ranges from 386-397 ºC. When a binary blend of (2) and (3) (with the former in the minority) is co-cured with (4), an excellent balance of properties is achieved with liquid processing, a Tg greater than 400 C and onset of degradation of 425 ºC in static air. Kinetic analysis of DSC data using Ozawa and Kissinger methods yield activation energies of between 107- 112 kJ/mole for a binary blend of (1)90-(4)10, which is in good agreement with literature. Molecular dynamics simulation of the same blend in cured form gave a simulated glass transition temperature of 250 C that is in very close agreement with empirical DMTA data.

The DNA repair enzyme AAG has been shown in mice to promote tissue necrosis in response to ischaemic reperfusion or treatment with alkylating agents. A chemical probe inhibitor is required for investigations of the biological mechanism causing this phenomenon and as a lead for drugs that are potentially protective against tissue damage from organ failure and transplantation, and alkylative chemotherapy. Herein, we describe the rationale behind the choice of arylmethylpyrrolidines as appropriate aza-nucleoside mimics for an inhibitor followed by their synthesis and the first use of a microplate-based assay for quantification of their inhibition of AAG. We finally report the discovery of an imidazol-4-ylmethylpyrrolidine as a fragment-sized, weak inhibitor of AAG.

The degradation behaviour of five polybenzoxazines (PBZs) is studied using pyrolysis-GC/MS. Upon heating to 800 °C in helium the PBZs generate a variety of similar pyrolysis products including aniline (the major product in all cases), substituted phenols, acridine, and 9-vinylcarbazole. During the initial stages of heating (200–300 °C) aniline is the dominant pyrolysis product; from 350 °C onwards substituted phenols are released, particularly 2-methylphenol and 2,6-dimethyl phenol. The same major species are produced on heating in air, but in addition isocyanatobenzene is observed which results from the oxidation of Mannich bridges, along with a number of sulphurous species from the monomer containing a thioether bridge. This suggests that sulphur is more likely to be retained in the char in a helium atmosphere, but takes part in oxidative reactions to form pyrolysis fragments in air. During the ramped temperature cycles in both air and helium atmospheres the release of aniline was observed to rise, fall and then to rise again. This may be due a combination of the very high heating rate, poor thermal conduction of the polymer and the availability of the Mannich bridges to undergo breakdown.

Background—T NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism (SNP) C242T of the p22phox subunit of NADPH oxidase has been reported to be negatively associated with coronary heart disease (CHD) and may predict disease prevalence. However, the underlying mechanisms remain unknown. Methods and Results—Using computer molecular modelling we discovered that C242T SNP causes significant structural changes in the extracellular loop of p22phox and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22phox reduced significantly Nox2 expression but had no significant effect on basal endothelial O2 .- production or the expression of Nox1 and Nox4. When cells were stimulated with TNFĮ (or high glucose), C242T p22phox inhibited significantly TNFĮ- induced Nox2 maturation, O2 .- production, MAPK and NFțB activation and inflammation (all p

Three cyanate ester monomer or oligomer species: 2,2-bis(4-cyanatophenyl)propane 1, 1-1-bis(4-dicyanatophenyl)ethane 2, and the oligomeric phenolic cyanate 3, are blended in various ratios to form binary mixtures (18 in total), formulated with copper(II) acetylacetonate (200 ppm) in dodecylphenol (1 % w/v active copper suspension) and cured (3 Kmin-1 to 150 °C + 1 hour; 3 Kmin-1 to 200 °C + 3 hours) followed by a post cure (3 Kmin-1 to 260 °C + 1 hour). Cured copolymers were exposed to environments of elevated relative humidity (75 % RH) and parallel immersion testing in H2O, H2SO4 (10 %) and NaOH (10 %) at 25 °C for a period of up to 2 years and accelerated ageing in boiling water (14 days). Periodic measurements are made of moisture gain along with infrared spectra and compared with cured homopolymers. Changes in mass are recorded periodically throughout exposure, prior to destructive thermo-mechanical analyses. Dynamic mechanical thermal analysis data comparing neat and exposed blends demonstrate the detrimental effect of moisture ingress whilst data from thermogravimetric analysis demonstrate no change in degradation onset between neat and exposed materials. An optimised blend of 1:1 of monomer units 1 and 2 was found to absorb less moisture than blends of different stoichiometry or between other respective monomeric units, consequently limiting the deleterious effect of moisture ingress.

Materials science is beginning to adopt computational simulation to eliminate laboratory trial and error campaigns—much like the pharmaceutical industry of 40 years ago. To further computational materials discovery, new methodology must be developed that enables rapid and accurate testing on accessible computational hardware. To this end, the authors utilise a novel methodology concept of intermediate molecules as a starting point, for which they propose the term ‘symthon’a rather than conventional monomers. The use of symthons eliminates the initial monomer bonding phase, reducing the number of iterations required in the simulation, thereby reducing the runtime. A novel approach to molecular dynamics, with an NVT (Canonical) ensemble and variable unit cell geometry, was used to generate structures with differing physical and thermal properties. Additional script methods were designed and tested, which enabled a high degree of cure in all sampled structures. This simulation has been trialled on large-scale atomistic models of phenolic resins, based on a range of stoichiometric ratios of formaldehyde and phenol. Density and glass transition temperature values were produced, and found to be in good agreement with empirical data and other simulated values in the literature. The runtime of the simulation was a key consideration in script design; cured models can be produced in under 24 h on modest hardware. The use of symthons has been shown as a viable methodology to reduce simulation runtime whilst generating accurate models.

The technique of Quantitative Structure Property Relationships has been applied to the glass transition temperatures of polyarylethersulphones. A general equation is reported that calculates the glass transition temperatures with acceptable accuracy (correlation coefficients of between 90–67%, indicating an error of 10–30% with regard to experimentally determined values) for a series of 42 reported polyarylethersulphones. This method is quite simple in assumption and relies on a relatively small number of parameters associated with the structural unit of the polymer: the number of rotatable bonds, the dipole moment, the heat of formation, the HOMO eigenvalue, the molar mass and molar volume. For smaller subsets of the main group (based on families of derivatives containing different substituents) the model can be simplified further to an equation that uses the volume of the substituents as the principal variable.

The crystal structure of a commercially available form of human recombinant (HR) insulin, Insugen (I), used in the treatment of diabetes has been determined to 0.92 Å resolution using low temperature, 100 K, synchrotron X-ray data collected at 16,000 keV (λ = 0.77 Å). Refinement carried out with anisotropic displacement parameters, removal of main-chain stereochemical restraints, inclusion of H atoms in calculated positions, and 220 water molecules, converged to a final value of R = 0.1112 and Rfree = 0.1466. The structure includes what is thought to be an ordered propanol molecule (POL) only in chain D(4) and a solvated acetate molecule (ACT) coordinated to the Zn atom only in chain B(2). Possible origins and consequences of the propanol and acetate molecules are discussed. Three types of amino acid representation in the electron density are examined in detail: (i) sharp with very clearly resolved features; (ii) well resolved but clearly divided into two conformations which are well behaved in the refinement, both having high quality geometry; (iii) poor density and difficult or impossible to model. An example of type (ii) is observed for the intra-chain disulphide bridge in chain C(3) between Sγ6–Sγ11 which has two clear conformations with relative refined occupancies of 0.8 and 0.2, respectively. In contrast the corresponding S–S bridge in chain A(1) shows one clearly defined conformation. A molecular dynamics study has provided a rational explanation of this difference between chains A and C. More generally, differences in the electron density features between corresponding residues in chains A and C and chains B and D is a common observation in the Insugen (I) structure and these effects are discussed in detail. The crystal structure, also at 0.92 Å and 100 K, of a second commercially available form of human recombinant insulin, Intergen (II), deposited in the Protein Data Bank as 3W7Y which remains otherwise unpublished is compared here with the Insugen (I) structure. In the Intergen (II) structure there is no solvated propanol or acetate molecule. The electron density of Intergen (II), however, does also exhibit the three types of amino acid representations as in Insugen (I). These effects do not necessarily correspond between chains A and C or chains B and D in Intergen (II), or between corresponding residues in Insugen (I). The results of this comparison are reported.

The construction of molecular models of crosslinked polymers is an area of some difficulty and considerable interest. We report here a new method of constructing these models and validate the method by modelling three epoxy systems based on the epoxy monomers bisphenol F diglycidyl ether (BFDGE) and triglycidyl-p-amino phenol (TGAP) with the curing agent diamino diphenyl sulphone (DDS). The main emphasis of the work concerns the improvement of the techniques for the molecular simulation of these epoxies and specific attention is paid towards model construction techniques, including automated model building and prediction of glass transition temperatures (T(g)). Typical models comprise some 4200-4600 atoms (ca. 120-130 monomers). In a parallel empirical study, these systems have been cast, cured and analysed by dynamic mechanical thermal analysis (DMTA) to measure T(g). Results for the three epoxy systems yield good agreement with experimental T(g) ranges of 200-220°C, 270-285°C and 285-290°C with corresponding simulated ranges of 210-230°C, 250-300°C, and 250-300°C respectively.

Simple molecular docking calculations on quercetin, kojic acid and diethylcarbamatodithoic acid using the software package MOE are shown to be close to the geometries reported in the X-ray crystal structures of the protein co-crystallised with the respective ligands. Furthermore DFT optimization of the docked conformations is shown to reproduce the essential features of previous studies on quercetin, showing that docking can be used to provide good starting structures for mechanistic study. The flavone ligand, lacking the hydroxyl group of the quercetin is shown by docking to be unable to approach closely the copper atom, indicating the necessity of the presence of the hydroxyl group and providing a prediction of the likely binding environment of this ligand.

The hydrogen bonding of bovine ribonuclease A derived from the high resolution X-ray structure has been studied in detail. Correlations have been examined for main-chain-main-chain hydrogen bond angles, torsion angles and distances, respectively. Differences are found consistently for correlations associated with α-helix and β-sheet, respectively. Ten of the 124 side-chains have four or more hydrogen bond contacts; two, including Glu-101, have five or more. Three potential COH, three NX and three potential side-chain H-bonds fail to form. A search for highly inaccessible buried residues resulted in nine outstanding examples, all of which are conserved across 38 known mammalian ribonuclease A sequences, indicating the importance of these residues for structural stability. Of the two histidines in the active site, His-12 has five hydrogen bonds and His-119 three. The conformational space accessible to these two catalytically important residues studied by means of simple non-bonded contact energy calcualtions confirms the existence of two alternative, interchangeable locations of His-119, while His-12 is locked in a local energy minimum.

The degradation behavior of five polybenzoxazines is studied and the effect of selected experimental parameters (particle size, heating rate, and atmosphere) on the nature of the degradation pathway is examined. The particle size within the samples (systematically varied in four discrete size ranges: 250 mu m) influences the progress of the early stage in the degradation mechanism (the cleavage of the bridging groups) such that the smaller particles are less stable, but the latter stages of the degradation mechanism remain largely unaffected. In contrast, the change in heating rate (5, 10, 15, 20 K min(-1)) of the thermogravimetric analysis has little effect on the first step in the degradation mechanism, but has a strong influence on the progress of the ring breakdown mechanism. Molecular simulation is shown to reproduce the thermo-mechanical behavior of the polybenzoxazine of bisphenol A/aniline very well, with the nuances of the glass transition and degradation onset temperatures simulated very closely (e.g., within 10 degrees C of the degradation experiment at a mass loss of 5 wt %). Quantitative structure property relationships are shown to predict the experimental char yields for all the polybenzoxazines studied within the data set, with the calculated values for the polymers based solely on the volume and surface area of the monomer structures.

The anisotropic displacements of selected rigid groups in bovine ribonuclease A have been refined from X-ray diffraction data by the application of the rigid-body TLS model. The rigid groups chosen were the side chains of tyrosine, histidine and phenylalanine and the planar side chains of aspartic acid, glutamic acid, glutamine, asparagine and arginine. The method has also been applied to the co-crystallizing active-site sulfate anion. This has enabled the description of the motion of the above-mentioned side-chain atoms by anisotropic displacement ellipsoids from a 1.45 A refinement. The hydrophobic side groups in the protein core show mainly translational motion, with mean-square librations of 20 deg2 which are similar to those found in some close-packed crystals of small organic molecules. Librational displacements are much more significant in the hydrophilic side groups where their magnitudes can be correlated with solvent accessibility. Large librations of some solvent exposed side chains correspond with the breakdown of a simple TLS model and the existence of multiple orientations of the side groups. The TLS model has also been applied to the whole protein molecule and shows that the average motion is approximately isotropic with little librational character.

The iron solution chemistry of the FeCl 3-gallocyanine system has been investigated by pH titration, UV visible spectroscopy and Mössbauer spectroscopy. Iron reduction was found in the pH range 2–5 and photo-reduction of the iron(III) present was also noted. Due to the instability of the species present in solution, the use of gallocyanine as a spectrophotometric indicator in iron systems is not encouraged. The iron-gallocyanine system was proposed as a potential model of the photosensitive anti-cancer drug, Bleomycin.

The energies and structures of neutral benzenoid and neutral quinonoid polyphenylenes in the gas phase were calculated at the ab initio and semi-empirical levels for oligomers containing up to 11 rings as a function of the torsion angles between consecutive aromatic rings. In the gas-phase poly( p-phenylene) (PPP) simulations, a transition to the aromatic benzenoid structure occurs in the centre of chains as short as about six to seven rings. The development of electronic properties such as ionisation potential, the carbon–carbon bond length between rings, the band gap and width of the highest occupied bands were studied. On going from a coplanar to a perpendicular conformation, qualitatively, the ionisation potential and band gap values increase and the band widths of the highest occupied bands decrease. Molecular mechanics simulations were used to model the crystal structures of PPP oligomers using Lennard–Jones and sinusoidal torsion potentials, with parameters derived initially from the gas-phase calculations. These solid state simulations reproduced known crystal structures and predictions are made for the crystal structures of PPP oligomers up to a degree of polymerisation of 11. The crystal packing forces the PPP molecules to be planar, hence increasing conductivity in the solid state. Interestingly, there is an anomaly in the packing energy results for the sexiphenylene case which is in accord with the gas phase calculations.

The possible role of the gamma-glutamyl cycle in the transport of amino acids, using the Caco-2 cell monolayer as an in vitro model of the small intestine, has been investigated. The transport of [2- 3H]glycine and [2- 3H]glycylglycine through the Caco-2 monolayer has been shown to occur by two modes of action. Active transport is unidirectional from apical to basolateral region and is a carrier mediated system. The enzyme gamma-glutamyl transpeptidase seems to be involved in this process, since when the enzyme is inhibited, the active transport is also inhibited. However transport still takes place, and this occurs by a slower non-active process, which is bidirectional and is mediated by passive diffusion. The rate of transport of [2- 3H]glycylglycine and [2- 3H]glycine were 585 (±24) and 287 (±16) pmolcm −2min −1 respectively, while the non-active transport takes place at 87 (±6) pmolcm −2min −1. Thus, amino acid translocation in Caco-2 cells is shown to occur by two methods, one of which involves the gamma-glutamyl cycle.

Selected bond distances and angles obtained for BA-a using Materials Studio (for the given conformations in Figure 1 ). (DOC)

Multiple correlation coefficient R  = 0.688.Coefficient of the multiple determination R2 = 0.474.Adjusted R2 = 0.360.Standard error  = 35.248.

This study concentrates on the important conducting polymer, polypyrrole. Detailed atomistic molecular models have been developed with the help of ab initio and semi-empirical quantum mechanical calculations. The vibrational spectra of isolated pyrrole monomers and oligomers from n = 1 and 2, where n is the number of structural repeat units used, have been computed using the ab initio 3-21G basis set. The results obtained are compared with data for the case of oligomers with n = 2-5 for both neutral benzenoid and quinonoid oligopyrroles, from semi-empirical predictions obtained by AM1 and PM3. The trends in the computed harmonic force fields, vibrational frequencies and intensities are monitored as a function of the chain length. The data are analysed in conjunction with the trends in computed equilibrium geometries. Also the examination of the heat of formation of these two degenerate forms (quinonoid and benzenoid) has been conducted with respect to increases in the number of rings and the change of methods from AM1 to PM3.

The crystal structure of the title compound [Zr(pc) 2 ] has been solved by X-ray diffraction techniques. The cell is triclinic, P 1&cmb.macr;; a = 13.410(2)Å, b = 13.400(7)Å, c = 16.340(11)Å, α= 68.68(1)°, β = 65.92(1)°, γ = 74.74(1)°, R = 0.039 and R ′= 0.058 for 6576 reflections. The infrared spectrum and details of the solvent dependence of the electronic absorption spectrum are also given. [Zr(pc) 2 ] has the most distorted rings of all the metal bisphthalocyanines so far reported. The distortion is primarily caused by the Zr-N distances (average 2.30 Å), which though long for such Zr bonding, are very small when compared to other M-N bonds in similar structures. Cyclic voltammograms of [Zr(pc) 2 ] are presented and discussed. The distorted structure has a detrimental effect on the electrochromic properties of the molecule, aiding decomposition during oxidation.

Mössbauer spectroscopic studies on the title complex and that of its pyridinium analogue are reported on samples of these materials previously heated in the temperature range 18–200 °C. The title complex is shown to be reduced to a mixture of iron(II) compounds at 200 °C. The use of ferrocenium as a smoke suppressant appears to have no advantage over that of ferrocene, as it is converted to ferrocene when heated in air in the presence of light.

An epoxy resin based on the difunctional diglycidyl ether of bisphenol A (DGEBA) is reacted thermally in the presence of a series of 1,3-dialkylimidazolium based ionic liquids comprising the common cation (1-ethy1-3-methylimidazolium) and an anion (acetate, dicyanamide, or thiocyanate). Dynamic differential scanning calorimetry was used to analyse the formulations comprising DGEBA and the ionic liquid where it was revealed that the lowest and highest temperature for the onset of reaction were observed for formulations with 1-ethyl-3-methylimidazolium acetate and 1-ethyl-3-methylimidazolium dicyanamide respectively. Cured glass transition temperatures range from 151 to 175 degrees C, depending on the anion used. Gelation behaviour is also dependent on the nature of the anion, with the acetate promoting gelation most quickly, whereas the dicyanamide is least reactive. Kinetic analysis of the cure reactions yield consistent results (R-2 > 0.99) using the Ozawa method (E-a = 74-98 kJ/mol) and are in good agreement with previous studies on imidazoles.

The X-ray structure of the inhibitor complex of bovine ribonuclease A with cytidylic acid (2′-CMP) has been determined at 2.3 Å (1 Å = 0.1 nm) resolution and refined by restrained least-squares refinement to R = 0.132 for 5650 reflections. Incorporation of the inhibitor molecule has occurred with little disturbance of the protein main-chain atoms, although significant displacement of some side-chain atoms has occurred, particularly in the region of the active site. The binding of 2′-CMP to ribonuclease A is different from that of the related cytidine- N(3)-oxide 2′-phosphate, which has an extra oxygen on N(3) of the cytidine base. The PO 4 2− group is held by hydrogen bond interactions to the side-groups of His12, Glu11 and His119. Thr45 is involved in stabilizing the enzyme-ligand complex by forming hydrogen bond interactions between O(γ) and the pyrimidine base N(3) atom and between the main-chain N(45) and O(2) of the base. Phe120 is much closer to the inhibitor than in the cytidine N(3)-oxide 2′-phosphate structure.

The reaction between phenyglycidyl ether and a series of primary aromatic amines has been studied under conditions where [epoxide]&z.Gtc;[amines](conditions which we categorise as ideal) using a radio-high-performance liquid chromatography (HPLC) method that is shown to be very versatile and capable of wide application. The results show that the small amounts of water present in the reaction medium possess a catalytic role as do the hydroxylated species formed during the course of the reaction. The detailed information so obtained makes it possible to use numerical techniques so that a comparison can be made between a theoretical model and the actual experimental behaviour.

A model of angiogenin has been prepared by homology modelling, based upon the structure of ribonuclease A. This model has been used to postulate an inhibitor based upon the angiostatic agent TAN1120. The complex of ribonuclease A with a dinucleotide has been modelled and used as a guide to the binding orientation of daunomycin--the closest TAN1120 analogue for which the crystal structure and stereochemistry are available.

The use of a combination of computer modelling and tritium radiolabelling is described as a technique for the investigation of the kinetics and mechanism of the autocatalytic reactions occurring in epoxy resin cure. Rate constants for substituted anilines reacting with phenylglycidylether have been derived and the effect of steric hindrance investigated. The program is described and its use in the explanation and understanding of the experimental data is illustrated.

Bi- and tri-aromatic compounds of the formula (I) wherein R1 to RIO and X are as defined, are Nox2 inhibitors that are useful as medicaments for the treatment of a disease or condition selected from: cardiovascular diseases, respiratory diseases, inflammatory diseases, cancers, ageing and age related disorders, kidney diseases, neurodegenerative diseases, diabetes and conditions associated with diabetes. The compounds, their preparation and pharmaceutical compositions comprising them are disclosed.

This article describes the objectives and rationale of the degree course in Computer-Aided Chemistry at the University of Surrey. The course, which is the first of its kind, represents a sharp break with the past in that industry was intimately involved in the early stages of the planning as well as providing subsequent support; furthermore, much of the teaching is done via a workshop approach. The course aims to produce high-calibre chemists, particularly of the analytical kind, with a firm foundation in computing and having benefited from the close collaboration and cooperation of industry.

The industrial cure of epoxy resins requires reliable kinetic models of the chemical reactions which are taking place during cure. We demonstrate here how a combination of novel radiochemical and numerical modelling techniques can provide information on both the rates and the important chemical details of the mechanism of epoxy cure when applied to more tractable chemical models.

A new algorithm is developed which implements the Monte Carlo annealing method and is used to model and minimize linear, single and double stranded B-DNA sequences. The preliminary B-DNA structures are modeled using initial structures obtained from the Brookhaven database. The model contains structural details at the atomic level and is therefore more elaborate and accurate than the pseudo-atomic and elastomechanical models. The minimization concerns the entire chain length and not only local nucleotide complexes. A variety of DNA sequences (coding or non-coding, random or real, homogeneous or heterogeneous) are investigated in the range of 20-40 base pairs. The potential energy function is written in terms of a set of internal coordinates defined to account for the helical parameters such as twist, tilt and rise, which are important parameters for the description of the global shape of any type of DNA or RNA molecule. The force field used is composed of a limited number of bonded and non-bonded interactions such as bond stretch, angle bend and Lennard-Jones interactions with the Dreiding II force field parameter set used for these interactions. From the minimized structures the angles between Phosphate-Oxygen-Carbon " A 1 " and Oxygen-Phosphate-Oxygen " A 2 " and the average helical twist were calculated. For single strands it is shown that the bond angles are A 1 =107 - 1° and A 2 =122 - 1°, while the helical twist is 37.8 - 1°. For double stranded DNA our model predicts the helical twist of h =35.5 - 2° well, in the A strand, while the prediction is less accurate, h =47 - 2° for the complementary strand B. The average values for the angles A 1 and A 2 are 130 - 1° and 150 - 3° for strand A and 102 - 4° and 123 - 5° for strand B. The reason for this discrepancy is attributed to the different conformations initially adopted by the sugars in the A and B strands.

A software algorithm has been developed to investigate the folding process in B-DNA structures in vacuum under a simple and accurate force field. This algorithm models linear double stranded B-DNA sequences based on a local, sequential minimization procedure. The original B-DNA structures were modeled using initial nucleotide structures taken from the Brookhaven database. The models contain information at the atomic level allowing one to investigate as accurately as possible the structure and characteristics of the resulting DNA structures. A variety of DNA sequences and sizes were investigated containing coding and non-coding, random and real, homogeneous or heterogeneous sequences in the range of 2 to 40 base pairs. The force field contains terms such as angle bend, Lennard-Jones, electrostatic interactions and hydrogen bonding which are set up using the Dreiding II force field and defined to account for the helical parameters such as twist, tilt and rise. A close comparison was made between this local minimization algorithm and a global one (previously published) in order to find out advantages and disadvantages of the different methods. From the comparison, this algorithm gives better and faster results than the previous method, allowing one to minimize larger DNA segments. DNA segments with a length of 40 bases need approximately 4 h, while 2.5 weeks are needed with the previous method. After each minimization the angles between phosphate-oxygen-carbon A1, the oxygen-phosphate-oxygen A2 and the average helical twists were calculated. From the generated fragments it was found that the bond angles are A1=150 degrees +/-2 degrees and A2=130 degrees +/-10 degrees, while the helical twist is 36.6 degrees +/-2 degrees in the A strand and A1=150 degrees +/-6 degrees and A2=130+/-6 degrees with helical twist 39.6 degrees +/-2 degrees in the B strand for the DNA segment with the same sequence as the Dickerson dodecamer.

The effect on the calculated ab initio GIAO 13C, 17O and 1H nuclear shielding parameters from secondary interactions in the gellan polysaccharide chains via intra- and interchain hydrogen bonding and K +, Na + cation binding are investigated. Mulliken population analysis methods are used to quantify the strength of these interactions in terms of the changing molecular electronic structure as a function of basis set quality. The 3-21G, 4-31G, 6-31G, 4-31G∗∗ and 6-31G∗∗ basis sets have been tested in our calculations.

A complete description of the current version of RESTRAIN, a program primarily for the least‐squares refinement of macromolecular structures, is presented. This description announces the version that will be released to the academic community. The additional features present in this version are described in detail. The program is compared with two other macromolecular refinement programs. Finally information about documentation and availability is presented.

Selected Bond lengths of selected bond types in the PEK telechelic obtained using Materials Studio (for a single chain and twelve chains) at room temperature (for the given configurations). (DOC)

The anisotropic displacements of selected rigid groups in monoclinic papain have been refined from X-ray diffraction data by application of the rigid-body TLS model. The rigid groups chosen were the aromatic side chains of tryptophan, tyrosine, histidine and phenylalanine, and the planar carboxylic and guanidinium side chains of aspartic acid, glutamic acid, glutamine, asparagine and arginine. The derived translation and libration tensors have been compared with those previously derived for bovine ribonuclease A and provide evidence for different modes and anisotropies of displacement over the two proteins.

Ab initio, GIAO and IGLO, nuclear shielding calculations are performed on each of the four pyranose ring residues of the tetrasaccharide repeating unit in a single chain of the gellan polysaccharide, [→ 3)- d-Glcp-(1 → 4)-β- d-GlcpA-(1 → 4)-β- d-Glcp-(1 → 4)-α- l-Rhap(1 n . The results provide an insight into the effects of the changing primary molecular electronic structure on the calculated 13C, 17O and 1H shieldings. In particular, the observed trends in the calculated isotropic ( σ i) shielding values are rationalised withi the framework of the localised molecular orbital shielding contributions and Mulliken population analyses (MPA).

A series of agonists to the rat muscarinic receptor have been docked computationally to the active site of a homology model of rat M1 muscarinic receptor. The agonists were modelled on the X-ray crystal structure of atropine, which is reported here and the docking studies are shown to reproduce correctly the order of experimental binding affinities for the agonists as well as indicate where there appear to be inconsistencies in the experimental data. The crystal and molecular structure of atropine (tropine tropate; alpha-[hydroxymethyl]benzeneacetic acid 8-methyl[3.2.1]oct-3-yl ester C17H23NO3) has been determined by X-ray crystallography using an automated Patterson search method, and refined by full-matrix least-squares to a final R of 0.0452 for 2701 independent observed reflections and 192 parameters using Mo Kalpha radiation, lambda=0.71073A at 150K. The compound crystallises in space group Fdd2 with Z=16 molecules per unit cell.

The product of reaction of ferrocene with iron( III ) chloride, previously formulated as ferrocenium trichloroferrate( II ), [Fe III (η-C 5 H 5 ) 2 ][Fe II Cl 3 ], is shown to be the µ-oxo compound [Fe III (η-C 5 H 5 ) 2 ] 2 [(Fe III Cl 3 ) 2 O].

This paper concentrates on two very important conducting polymers poly(p-phenylene) and polypyrrole. Detailed atomistic molecular models have been developed with the help of ab initio and semi-empirical quantum mechanical calculations using the Cerius 2 and WinMOPAC (version 6.0) programs. Their optimised geometry had been calculated and compared with experimental X-ray diffraction data. The simulated and experimental vibrational spectra of biphenyl as well as isolated pyrrole monomers and oligomers from n = 1 and 2, where n is the number of structural repeat units used, have been computed using the ab initio 3-21G basis set. The results obtained are compared with experimental data for the case of biphenyl and for oligomers with n = 2 to 5 for both neutral benzenoid and quinonoid oligopyrroles, from semi-empirical predictions obtained by AM1 and PM3. The trends in the computed harmonic force fields, vibrational frequencies and intensities are monitored as a function of the chain length. The data are analyzed in conjunction with the trends in computed equilibrium geometries.

Molecular simulations can measure strain in bond lengths, angles, torsion, and non-bonded interactions. High strain energy indicates a reactive and unstable molecule. Method 4-turn amylose and saturated FA models (C8-C22) were built using MOE2020.09 software. Molecular dynamics were simulated in water, with complexes containing 1 or 2 FAs per amylose helix. Results Conclusion The lower the energy, the more stable the molecule. • Double FA complexes are less stable than single FA complexes. • Trend: The stability increases from C8 and decreases from C14. • C10 single FA complexes have the lowest energy so are most likely to be stable, meaning they are a feasible candidate for practical use.

Polymeric materials modelling has the potential to rapidly accelerate the discovery of new materials due to the comparative ease of simulations compared to laboratory testing campaigns. High quality molecular dynamics simulation software, such as LAMMPS, are able to facilitate the transition from empirical to digitised chemistry. However, in order to fully benefit from the speed of simulations, tools need to be developed to automate the preprocessing stages required for modelling. AutoMapper is an open-source Python application that automates the generation of files required to use REACTER, a powerful polymer bonding package implemented within LAMMPS. To automate this process, the authors developed an iterative path search algorithm based on chemical graph theory to accurately map pre- and post-reaction polymerisation structures, and hence eliminating the bulk of the human effort previously required to run a simulation. AutoMapper requires minimal user input, is force field independent, and has shown marvellous performance on a wide range of polymerisation types.

A variety of two-dimensional (2D) nanomaterials, including graphene oxide and clays, are known to stabilize Pickering emulsions to fabricate structures for functions in sensors, catalysts, and encapsulation. We introduce here a novel Pickering emulsion using self-assembled amphiphilic triblock oligoglycine as the emulsifier. Peptide amphiphiles are more responsive to environmental changes (e.g., pH, temperature, and ionic strength) than inorganic 2D materials, which have a chemically rigid, in-plane structure. Noncovalent forces between the peptide molecules change with the environment, thereby imparting responsiveness. We provide new evidence that the biantennary oligoglycine, Gly4–NH–C10H20–NH–Gly4, self-assembles into 2D platelet structures, denoted as tectomers, in solution at a neutral buffered pH using small-angle X-ray scattering and molecular dynamics simulations. The molecules are stacked in the platelets with a linear conformation, rather than in a U-shape. We discovered that the lamellar oligoglycine platelets adsorbed at an oil/water interface and stabilized oil-in-water emulsions. This is the first report of 2D oligoglycine platelets being used as a Pickering stabilizer. The emulsions showed a strong pH response in an acidic environment. Thus, upon reducing the pH, the protonation of the terminal amino groups of the oligoglycine induced disassembly of the lamellar structure due to repulsive electrostatic forces, leading to emulsion destabilization. To demonstrate the application of the material, we show that a model active ingredient, β-carotene, in the oil is released upon decreasing the pH. Interestingly, in pH 9 buffer, the morphology of the oil droplets evolved over time, as the oligoglycine stabilizer created progressively a thicker interfacial layer. This demonstration opens a new route to use self-assembled synthetic peptide amphiphiles to stabilize Pickering emulsions, which can be significant for biomedical and pharmaceutical applications.

We examine the mechanism of pyrolysis and charring of large (> 10,000 atom) phenol-formaldehyde resin structures produced using pseudo-reaction curing techniques with formaldehyde/phenol ratios of 1.0, 1.5 and 2.0. We utilise Reactive Molecular Dynamics (RMD) with a hydrocarbon oxidation parameter set to simulate the high-temperature thermal decomposition of these resins at 1500, 2500 and 3500 K. Our results demonstrate that the periodic removal of volatile pyrolysis gasses from the simulation box allows us to achieve near complete carbonisation after only 2 ns of simulation time. The RMD simulations show that ring openings play a significantly larger role in thermal decomposition than has previously been reported. We also identify the major phases of phenolic pyrolysis and elucidate some of the possible mechanisms of fragment formation and graphitisation from the RMD trajectories and compute the thermal and mechanical properties of the final pyrolysed structures. [GRAPHICS] .

The Epithelial Sodium Channel/Degenerin (ENaC/DEG) family is a superfamily of sodium-selective channels that play diverse and important physiological roles in a wide variety of animal species. Despite their differences, they share a high homology in the pore region in which the ion discrimination takes place. Although ion selectivity has been studied for decades, the mechanisms underlying this selectivity for trimeric channels, and particularly for the ENaC/DEG family, are still poorly understood. This systematic review follows PRISMA guidelines and aims to determine the main components that govern ion selectivity in the ENaC/DEG family. In total, 27 papers from three online databases were included according to specific exclusion and inclusion criteria. It was found that the G/SxS selectivity filter (glycine/serine, non-conserved residue, serine) and other well conserved residues play a crucial role in ion selectivity. Depending on the ion type, residues with different properties are involved in ion permeability. For lithium against sodium, aromatic residues upstream of the selectivity filter seem to be important, whereas for sodium against potassium, negatively charged residues downstream of the selectivity filter seem to be important. This review provides new perspectives for further studies to unravel the mechanisms of ion selectivity.

Bisbenzoxazines form highly crosslinked, network structures with relatively high Tg (180oC+) and thermal oxidative stability but inherent brittleness (G1C = 168 J/m2) - limiting their applications. We have used synthetic polymer chemistry and molecular simulation to probe the structure/property relationships in model and commercial systems with the aim of understanding the factors governing toughness in these materials. Our previous experience, gained over 20 years, leads us to ensure that the molecular model represents as accurately as possible the real network, e.g. incorporating molecular defects derived from empirical data. We report the preparation and characterisation of selected bisbenzoxazine monomers chosen to exemplify both brittle and tough behaviour to provide a wide spectrum of mechanical characteristics and produce a wider understanding of the factors affecting brittleness. This enables us to design and execute the synthesis of new monomers with the potential for enhanced fracture toughness based on rational molecular design.

The p22phox is a key component of the cytochrome b558 of the NADPH oxidase (Nox), which by generating reactive oxygen species (ROS) is involved in the pathogenesis of cardiovascular disease. A p22phox polymorphism (C242T) has been found to reduce oxidative stress in the cardiovascular system and is negatively associated with the incidence of coronary heart disease (CHD). However, the mechanism involved remains unknown. In this study we used computer molecular modelling and bioinformatics to investigate the potential effect of C242T polymorphism on the 3-D protein structure of the p22phox. Based on the published sequence data of p22phox and the principle of regulated prediction algorithms, we found that p22phox consists of two domains: an N-terminal transmembrane domain (124 a.a.) and a C-terminal cytoplasmic domain (71 a.a.). In its most stable form, it has three e26 Heart September 2010 Vol 96 No 17 BSCR Spring 2010 Meeting Abstracts Downloaded from heart.bmj.com on January 31, 2012 - Published by group.bmj.com transmembrane helices leading to an extracellular N-terminus and an extracellular loop between helices two and three. The C242T polymorphism causes a change of His72 to Tyr72. This change results in significant morphological changes of the extracellular loop of the p22phox, which is in the putative interactive region of the p22phox with the catalytic subunit (Nox2). This may interfere with their association, and subsequently result in a reduced cytochrome b function and a reduced ROS production by NADPH oxidase. These results give us insight into the molecular mechanism of this polymorphism in reducing vascular oxidative stress and may explain how this polymorphism is linked with reduced incidence of CHD.

The p22phox is a key component of the cytochrome b558 of the NADPH oxidase (Nox), which by generating reactive oxygen species (ROS) is involved in the pathogenesis of cardiovascular disease. A p22phox polymorphism (C242T) has been found to reduce oxidative stress in the cardiovascular system and is negatively associated with the incidence of coronary heart disease (CHD). However, the mechanism involved remains unknown. In this study we used computer molecular modelling and bioinformatics to investigate the potential effect of C242T polymorphism on the 3-D protein structure of the p22phox. Based on the published sequence data of p22phox and the principle of regulated prediction algorithms, we found that p22phox consists of two domains: an N-terminal transmembrane domain (124 a.a.) and a C-terminal cytoplasmic domain (71 a.a.). In its most stable form, it has three transmembrane helices leading to an extracellular N-terminus and an extracellular loop between helices two and three. The C242T polymorphism causes a change of His72 to Tyr72. This change results in signifi cant morphological changes of the extracellular loop of the p22phox which is in the putative interactive region of the p22phox with the catalytic subunit (Nox2). This may interfere with their association, and subsequently result in a reduced cytochrome b function and a reduced ROS production by NADPH oxidase. These results give us insight into the molecular mechanism of this polymorphism in reducing vascular oxidative stress and may explain how this polymorphism is linked with reduced incidence of CHD.

Bi- and tri-aromatic compounds of the formula (I) wherein R1 to RIO and X are as defined, are Nox2 inhibitors that are useful as medicaments for the treatment of a disease or condition selected from: cardiovascular diseases, respiratory diseases, inflammatory diseases, cancers, ageing and age related disorders, kidney diseases, neurodegenerative diseases, diabetes and conditions associated with diabetes. The compounds, their preparation and pharmaceutical compositions comprising them are disclosed.