Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-β protein

The aggregation of amyloid β-protein (Aβ) is tightly linked to the pathogenesis of Alzheimer’s disease. Previous studies have found that three peptide inhibitors (i.e., KLVFF, VVIA, and LPFFD) can inhibit Aβ aggregation and alleviate Aβ-induced neurotoxicity. However, atomic details of binding modes and binding affinities between these peptide inhibitors and Aβ have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area (MM/PBSA) analysis, we examined the effect of three peptide inhibitors (KLVFF, VVIA, and LPFFD) on their sequence-specific interactions with Aβ and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to Aβ, in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with Aβ, consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and Aβ were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modification and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against Aβ aggregation.     

Maximum working temperature of refractory castables: do we really know how to evaluate it?

Refractoriness under load (RUL) tests are usually indicated to evaluate the maximum working temperature that refractory materials can withstand by measuring their linear dimensional change when subjected to compressive stress. Nevertheless, ASTM C832 and ISO 1893 standards do not point out which sort of samples (pre-fired or not) should be used during the measurements of this property. Thus, this study addresses the evaluation of different refractory castable systems, focusing on analyzing calcined (fired up to 600 °C for 5 h for the decomposition of the hydrated phases) or pre-fired (1550 °C for 5 h) samples in order to identify the effect of the material's thermal treatment on the RUL results. Additional properties (i.e. linear expansion change, apparent porosity and cold flexural strength after firing at different temperatures) of the designed compositions were also evaluated. Based on the results, it can be concluded that the maximum working temperature of monolithics should not be assessed via one single test (i.e. RUL), but only a set of techniques (RUL, dilatometry, assisted sintering, creep and others) can provide useful data to better understand the refractories performance. RUL measurements should be carried out after a preliminary sintering step of the castables (where the selected firing temperature might be as close as possible to the expected T_0.5) to enable most of the microstructural changes resulting from heating up and sintering could already have taken place. Furthermore, it is most likely that numerical solutions (modeling) could help to better understand and interpret the multivariable aspects of this complex issue. However, reliable and accurate values of the refractory properties (based on well-selected tests) must be fed to the software to permit calculations that yield meaningful and accurate results, and conclusions.     

Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends?

The adipocyte-derived ‘satiety promoting’ hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an ‘adipostat’, whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its ‘anti-obesity’ effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin’s metabolic effects while retaining leptin’s permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.     

Surface composition and possible rearrangement of disperse Pt and Rh catalysts: does the presence of carbon and oxygen contribute to different catalytic properties?

The surface composition of Rh and Pt blacks (as determined by XPS) shows carbon and oxygen impurities in the untreated state. Oxygen on Pt is present as adsorbed O as well as OH/H₂O groups and oxidized carbon. Rh was partly oxidized to Rh₂O₃, in agreement with UPS showing hardly any Fermi‐edge intensity in untreated Rh as opposed to untreated Pt. High Fermi‐edge intensities indicated a predominant metallic surface after an in situ treatment with H₂ at 483 K, increasing the purity (XPS) to ∼90%. This treatment reduced Rh to metal and removed its C impurity. Pt, in turn, retained much carbon after H₂ treatment, present mainly as graphitic carbon. A minor amount of CO was also detected, some of the O 1s peak belonging to it. The two metals were tested in methylcyclopentane reactions. Considering the necessity of carbon for nondegradative reactions and oxygen enhancing fragmentation, a correlation is suggested between the typical impurities of Pt and Rh and their respective catalytic propensities: the high fragmentation activity of Rh and the predominant nondegradative reactions to C₆ “ring opening products” on Pt. This revised version was published online in July 2006 with corrections to the Cover Date.     

New insights into the mechanistic details of the carbonic anhydrase cycle as derived from the model system [(NH(3))(3)Zn(OH)](+)/CO(2): how does the H(2)O/HCO(3)(-) replacement step occur?

The full reaction path for the conversion of carbon dioxide to hydrogencarbonate has been computed at the B3LYP/6-311+G** level, employing a [(NH(3))(3)Zn(OH)](+) model catalyst to mimic the active center of the enzyme. We paid special attention to the question of how the catalytic cycle might be closed by retrieval of the catalyst. The nucleophilic attack of the catalyst on CO(2) has a barrier of 5.7 kcal mol(-1) with inclusion of thermodynamic corrections and solvent effects and is probably the rate-determining step. This barrier corresponds well with prior experiments. The intermediate result is a Lindskog-type structure that prefers to stabilize itself via a rotation-like transition state to give a Lipscomb-type product, which is a monodentate hydrogencarbonate complex. By addition of a water molecule, a pentacoordinated adduct with pseudo-trigonal-bipyramidal geometry is formed. The water molecule occupies an equatorial position, whereas the hydrogencarbonate ion is axial. In this complex, proton transfer from the Zn-bound water molecule to the hydrogencarbonate ion is extremely facile (barrier 0.8 kcal mol(-1)), and yields the trans,trans-conformer of carbonic acid rather than hydrogencarbonate as the leaving group. The carbonic acid molecule is bound by a short O...H-O hydrogen bond to the catalyst [(NH(3))(3)Zn(OH)](+), in which the OH group is already replaced by that of an entering water molecule. After deprotonation of the carbonic acid through a proton relay to histidine 64, modeled here by ammonia, hydrogencarbonate might undergo an ion pair return to the catalyst prior to its final dissociation from the complex into the surrounding medium.