Metal binding to amyloid-β1–42: a ligand field molecular dynamics study

Ligand field molecular mechanics simulation has been used to model the interactions of copper(II) and platinum(II) with the amyloid-β1–42 peptide monomer. Molecular dynamics over several microseconds for both metalated systems are compared to analogous results for the free peptide. Significant differences in structural parameters are observed, both between Cu and Pt bound systems as well as between free and metal-bound peptide. Both metals stabilize the formation of helices in the peptide as well as reducing the content of β secondary structural elements compared to the unbound monomer. This is in agreement with experimental reports of metals reducing β-sheet structures, leading to formation of amorphous aggregates over amyloid fibrils. The shape and size of the peptide structures also undergo noteworthy change, with the free peptide exhibiting globular-like structure, platinum(II) system adopting extended structures, and copper(II) system resulting in a mixture of conformations similar to both of these. Salt bridge networks exhibit major differences: the Asp23-Lys28 salt bridge, known to be important in fibril formation, has a differing distance profile within all three systems studied. Salt bridges in the metal binding region of the peptide are strongly altered; in particular, the Arg5-Asp7 salt bridge, which has an occurrence of 71% in the free peptide, is reduced to zero in the presence of both metals

Benchmarking of copper(II) LFMM parameters for studying amyloid-β peptides

Ligand field molecular mechanics (LFMM) parameters have been benchmarked for copper (II) bound to the amyloid-β1–16 peptide fragment. Several density functional theory (DFT) optimised small test models, representative of different possible copper coordination modes, have been used to test the accuracy of the LFMM copper bond lengths and angles, resulting in errors typically less than 0.1 Å and 5°. Ligand field molecular dynamics (LFMD) simulations have been carried out on the copper bound amyloid-β1–16 peptide and snapshots extracted from the subsequent trajectory. Snapshots have been optimised using DFT and the semi-empirical PM7 method resulting in good agreement against the LFMM calculated geometry. Analysis of substructures within snapshots shows that the larger contribution of geometrical difference, as measured by RMSD, lies within the peptide backbone, arising from differences in DFT and AMBER, and the copper coordination sphere is reproduced well by LFMM. PM7 performs excellently against LFMM with an average RMSD of 0.2 Å over 21 tested snapshots. Further analysis of the LFMD trajectory shows that copper bond lengths and angles have only small deviations from average values, with the exception of a carbonyl moiety from the N-terminus, which can act as a weakly bound fifth ligand

Ligand field molecular dynamics simulation of Pt(II)-phenanthroline binding to N-terminal fragment of amyloid-β peptide

We report microsecond timescale molecular dynamics simulation of the complex formed between Pt(II)-phenanthroline and the 16 N-terminal residues of the Aβ peptide that is implicated in the onset of Alzheimer’s disease, along with equivalent simulations of the metal-free peptide. Simulations from a variety of starting points reach equilibrium within 100 ns, as judged by root mean square deviation and radius of gyration. Platinum-bound peptides deviate rather more from starting points, and adopt structures with larger radius of gyration, than their metal-free counterparts. Residues bound directly to Pt show smaller fluctuation, but others actually move more in the Pt-bound peptide. Hydrogen bonding within the peptide is disrupted by binding of Pt, whereas the presence of salt-bridges are enhanced

Effect of different storage conditions on analytical and sensory quality of thermally processed milk based germinated Foxtail millet porridge

Foxtail millet porridge was prepared using germinated grains and milk and was evaluated for its storage stability after thermal processing at Ultra High Temperatures (UHT) of 142 oC for 5 s and Retort processing temperatures of 121.5 oC for 15 min. Various physical, chemical and microbial changes of the porridge were studied for a storage period of 180 days at 25 ± 1 oC. Using consumer perception and survival analysis, the predicted shelf life of the UHT treated and retort processed foxtail millet porridge samples stored at 25 ± 1 oC was found to be 186 ± 9 days and 245 ± 15 days, respectively. Also, data from consumer liking, profiling, physical, chemical and microbial parameters showed significant changes (p < 0.05) in the thermally treated packaged porridge samples over time. As the consumer overall acceptability decreased, the detection of positive attributes (Thick and uniformly coloured texture and appearance; grainy mouth texture; caramel taste and aroma) in the porridge decreased, while the detection of negative attributes (Uneven, decoloured, and curdled texture and appearance; sticky mouth texture; cooked, sour and off smell; cooked, sour and off taste) increased. The present study could establish a significant difference (p < 0.05) in the storage induced properties of UHT and retort processed porridge samples. The analytical evaluation of foxtail millet porridge found that UHT treated porridge was better in quality, but consumers preferred retort processed porridge

Exploring Spirituality in Teaching Within a Christian School Context Through Collaborative Action Research

This article reports on a collaborative action research project conducted in New Zealand, during 2012, exploring spirituality in teaching within a Christian school context. The experienced primary school teacher participant chose to take action around the issue of personal fear and insecurity which were believed to be hindering professional growth and relationships. Through self-directed inquiry, critical reflective journaling, Bible study, fellowship and prayer with trusted friends, the teacher experienced a renewed sense of peace and freedom in Christ. This personal transformation was believed to be influential on subsequent professional practice, assisting the teacher to become more relational, responsive and compassionate. The findings provide a rich description of the participant’s spirituality, the lived reality of a person’s spiritual life. This report will be of interest to teachers, teacher-leaders and teacher-educators who desire to explore Christian spirituality through practitioner-led inquiry

Improved catalytic activity of ruthenium–arene complexes in the reduction of NAD+

A series of neutral Ru-II half-sandwich complexes of the type [(eta(6)-arene)Ru(N,N')Cl] where the arene is para-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), or benzene (bn) and N,N' is N-(2-aminoethyl) -4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-4-toluenesulfonamide (TsEn), or N-(2-aminoethyl)-methylenesulfonamide (MsEn) were synthesized and characterized. X-ray crystal structures of [(p-cym)Ru(MsEn)Cl] (1), [(hmb)Ru(TsEn)Cl] (5), [(hmb)Ru(TfEn)Cl] (6), [(bip)Ru(MsEn)Cl] (7), and [(bip)Ru(TsEn)Cl] (8) have been determined. The complexes can regioselectively catalyze the transfer hydrogenation of NAD(+) to give 1,4-NADH in the presence of formate. The turnover frequencies (TOF) when the arene is varied decrease in the order bn > bip > p-cym > hmb for complexes with the same N,N' chelating ligand. The TOF decreased with variation in the N,N' chelating ligand in the order TfEn > TsEn > MsEn for a given arene. [(bn)Ru(TfEn)Cl] (12) was the most active, with a TOP of 10.4 h(-1). The effects of NAD(+) and formate concentration on the reaction rates were determined for [(p-cym)Ru(TsEn)Cl] (2). Isotope studies implicated the formation of [(arene)Ru(N,N')(H)] as the rate-limiting step. The coordination of formate and subsequent CO2 elimination to generate the hydride were modeled computationally by density functional theory (DFT). CO2 elimination occurs via a two-step process with the coordinated formate first twisting to present its hydrogen toward the metal center. The computed barriers for CO2 release for arene = benzene follow the order MsEn > TsEn > TfEn, and for the Ms En system the barrier followed bn < hmb, both consistent with the observed rates. The effect of methanol on transfer hydrogenation rates in aqueous solution was investigated. A study of pH dependence of the reaction in D2O gave the optimum pH* as 7.2 with a TOF of 1.58 h(-1) for 2. The series of compounds reported here show an improvement in the catalytic activity by an order of magnitude compared to the ethylenediamine analogues

Object Relations in the Museum: A Psychosocial Perspective

This article theorises museum engagement from a psychosocial perspective. With the aid of selected concepts from object relations theory, it explains how the museum visitor can establish a personal relation to museum objects, making use of them as an ‘aesthetic third’ to symbolise experience. Since such objects are at the same time cultural resources, interacting with them helps the individual to feel part of a shared culture. The article elaborates an example drawn from a research project that aimed to make museum collections available to people with physical and mental health problems. It draws on the work of the British psychoanalysts Donald Winnicott and Wilfred Bion to explain the salience of the concepts of object use, potential space, containment and reverie within a museum context. It also refers to the work of the contemporary psychoanalyst Christopher Bollas on how objects can become evocative for individuals both by virtue of their intrinsic qualities and by the way they are used to express personal idiom

Solid-state interconversions: Unique 100% reversible transformations between the ground and metastable states in single-crystals of a series of nickel( II) nitro complexes

The solid-state, low-temperature linkage isomerism in a series of five square planar group 10 phosphino nitro complexes have been investigated by a combination of photocrystallographic experiments, Raman spectroscopy and computer modelling. The factors influencing the reversible solid-state interconversion between the nitro and nitrito structural isomers have also been investigated, providing insight into the dynamics of this process. The cis-[Ni(dcpe)(NO2)2] (1) and cis-[Ni(dppe)(NO2)2] (2) complexes show reversible 100 % interconversion between the η1-NO2 nitro isomer and the η1-ONO nitrito form when single-crystals are irradiated with 400 nm light at 100 K. Variable temperature photocrystallographic studies for these complexes established that the metastable nitrito isomer reverted to the ground-state nitro isomer at temperatures above 180 K. By comparison, the related trans complex [Ni(PCy3)2(NO2)2] (3) showed 82 % conversion under the same experimental conditions at 100 K. The level of conversion to the metastable nitrito isomers is further reduced when the nickel centre is replaced by palladium or platinum. Prolonged irradiation of the trans-[Pd(PCy3)2(NO2)2] (4) and trans-[Pt(PCy3)2(NO2)2] (5) with 400 nm light gives reversible conversions of 44 and 27 %, respectively, consistent with the slower kinetics associated with the heavier members of group 10. The mechanism of the interconversion has been investigated by theoretical calculations based on the model complex [Ni(dmpe)Cl(NO2)]

Theoretical study of the electronic spectra of small molecules that incorporate analogues of the copper-cysteine bond

The copper-sulphur bond which binds cysteinate to the metal centre is a key factor in the spectroscopy of blue copper proteins. We present theoretical calculations describing the electronically excited states of small molecules, including CuSH, CuSCH_3, (CH_3)_2SCuSH, (imidazole)-CuSH and (imidazole)_2-CuSH, derived from the active site of blue copper proteins that contain the copper-sulphur bond in order to identify small molecular systems that have electronic structure that is analogous to the active site of the proteins. Both neutral and cationic forms are studied, since these represent the reduced and oxidised forms of the protein, respectively. For CuSH and CuSH^+, excitation energies from time-dependent density functional theory with the B97-1 exchange-correlation functional agree well with the available experimental data and multireference configuration interaction calculations. For the positive ions, the singly occupied molecular orbital is formed from an antibonding combination of a 3d orbital on copper and a 3pπ orbital on sulphur, which is analogous to the protein. This leads several of the molecules to have qualitatively similar electronic spectra to the proteins. For the neutral molecules, changes in the nature of the low lying virtual orbitals leads the predicted electronic spectra to vary substantially between the different molecules. In particular, addition of a ligand bonded directly to copper results in the low-lying excited states observed in CuSH and CuSCH_33 to be absent or shifted to higher energies