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

Sources, Dangers and Treatments of Oily Soil Pollutants in Iraq

Oil pollution presents significant risks to living organism and human health because it can alter the ecosystem in rivers, seas, oceans, and pollutes air and soil. Oil, for example, can even reduce the efficiency of drinking water plants. Iraq suffers a lot from oil pollution as a result of wars that not only damage the oil infrastructures but also cause loss of thousand hectare of agriculture lands. In addition, oil pollution become primary factor that contribute to the electricity, fuel shortage and traffic jam problems. Oil pollution can be easily found in many parts of Iraq, even in main streets, houses and gardens due to the residents mismanagement and misuse of oily products. Therefore, the aim of this paper is to focus in detail about the sources and dangers of oil pollution on the environment and soil, as well as to provide some suggestions and measurements that can help in limiting the impact of oil pollution in Iraq

Stereochemical studies on protonated bridgehead amines. ^1H NMR determination of cis and trans B-C ring-fused structures for salts of hexahydropyrrolo [2,1-a] isoquinolines and related C ring homologs. Capture of unstable ring-fused structures in the solid state

Acid-addition salts of tricyclic isoquinolines 2a/b, 3a/b, 4a-4c, 5, 6a/b, 7, 8a/b, 9a/b, and 17a/b were studied by high-field ^1H NMR in CDCl_3 solution. Cis (e.g., 14 and 15 in Figure 1) and trans (e.g., 13)B-C ring-fused structures were identified by using the vicinal ^3J(CH-NH) coupling constants, which demonstrate a Karplus-like behavior. In some cases, we initially observed a trans form, which converted to a cis A form by N H proton exchange. For 4c.HBr, the exchange process was slowed by addition of trifluoroacetic acid. In many cases, cis A and cis B structures were preferred in solution. The pendant phenyl group exerted a strong influence on the preferred solution structure. Observation of the initial, unstable trans-fused structures was related to their capture in the solid state and release intact on dissolution. X-ray diffraction was performed on the HBr salts of 2a (B-C cis), 2b (B-C cis), and 4c (B-C trans). The result for 4c.HBr confirmed the connection between the initial trans form in solution and the solid state. For 17b.HCI two conformers, associated with hindered rotation about the bond connecting the 2,6-disubstituted phenyl group to the tricyclic array, were detected at ambient probe temperature; however, rotamers were not observed for either of the two forms (trans and cis A) of 17a.HBr. Two conformers were also found for 16b.HBr. Temperature-dependent behavior was recorded in the ^1H NMR spectra of 17b.HBr and 16b.HBr; the activation free energy for interconversion of conformers was estimated to be in the vicinity of 17 kcal/mol for the former and 14-15 kcal/mol for the latter. The ^1H NMR spectrum of butaclamol hydrochloride (20.HC1), a potent neuroleptic agent, in Me_2SO-d_6 revealed two species in a ratio of 81:19, which were assigned as trans and cis A forms, respectively. ^1H NMR data for various free bases are also presented and discussed. Empirical force field calculations on three model hydrocarbons are discussed from a perspective of finding an explanation for the configurational/conformational behavior of the bridgehead ammonium salts. Diverse literature examples of structures for protonated bridgehead amines are also discussed. A tentative rationale is suggested for the preference of cis A forms in some protonated tetrahydroisoquinoline derivatives

New evidence of the Giant Hyaena, Pachycrocuta brevirostris (Carnivora, Hyaenidae), from the Gladysvale Cave deposit (Plio-pleistocene, John Nash Nature Reserve, Gauteng, South Africa)

A well preserved cranium which represents the most complete skull of Pachycrocuta brevirostris (Carnivora, Hyaenidae) discovered in Africa, and a maxillary fragment from the Gladysvale Cave Deposit (John Nash Nature Reserve, Gauteng, South Africa) are described and compared to other fossil and extant hyaenid specimens from South Africa and Europe. In addition, some aspects of functional morphology in the hyaenid dentition are reconsidered and suggested to be directly related to the palaeoecological role of P. brevirostris.The Council's Research Committee, University of the Witwatersrand; National Research Foundation (NRF); Palaeo-Anthropology Scientific Trust (PAST); Swiss National Science FoundationGrant No. 31-43584.95;National Geographic Society; Adolph H. Schultz-Foundation; Georges & Antoine Claraz-Donatio

Solution structure of Mannobioses unravelled by means of Raman optical activity

Structural analysis of carbohydrates is a complicated endeavour, due to the complexity and diversity of the samples at hand. Herein, we apply a combined computational and experimental approach, employing molecular dynamics (MD) and density functional theory (DFT) calculations together with NMR and Raman optical activity (ROA) measurements, in the structural study of three mannobiose disaccharides, consisting of two mannoses with varying glycosidic linkages. The disaccharide structures make up the scaffold of high mannose glycans and are therefore important targets for structural analysis. Based on the MD population analysis and NMR, the major conformers of each mannobiose were identified and used as input for DFT analysis. By systematically varying the solvent models used to describe water interacting with the molecules and applying overlap integral analysis to the resulting calculational ROA spectra, we found that a full quantum mechanical/molecular mechanical approach is required for an optimal calculation of the ROA parameters. Subsequent normal mode analysis of the predicted vibrational modes was attempted in order to identify possible marker bands for glycosidic linkages. However, the normal mode vibrations of the mannobioses are completely delocalised, presumably due to conformational flexibility in these compounds, rendering the identification of isolated marker bands unfeasible

Recent seismic studies at the East Pacific Rise 8°20'–10°10'N and Endeavour Segment : insights into mid-ocean ridge hydrothermal and magmatic processes

Author Posting. © The Oceanography Society, 2012. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 25, no. 1 (2012): 100–112, doi:10.5670/oceanog.2012.08.As part of the suite of multidisciplinary investigations undertaken by the Ridge 2000 Program, new multichannel seismic studies of crustal structure were conducted at the East Pacific Rise (EPR) 8°20'–10°10'N and Endeavour Segment of the Juan de Fuca Ridge. These studies provide important insights into magmatic systems and hydrothermal flow in these regions, with broader implications for fast- and intermediate-spreading mid-ocean ridges. A mid-crust magma body is imaged beneath Endeavour Segment underlying all known vent fields, suggesting that prior notions of a tectonically driven hydrothermal system at this site can be ruled out. There is evidence at both sites that the axial magma body is segmented on a similar 5–20 km length scale, with implications for the geometry of high-temperature axial hydrothermal flow and for lava geochemistry. The new data provide the first seismic reflection images of magma sills in the crust away from the axial melt lens. These off-axis magma reservoirs are the likely source of more-evolved lavas typically sampled on the ridge flanks and may be associated with off-axis hydrothermal venting, which has recently been discovered within the EPR site. Clusters of seismic reflection events at the base of the crust are observed, and localized regions of thick Moho Transition Zone, with frozen or partially molten gabbro lenses embedded within mantle rocks, are inferred. Studies of the upper crust on the flanks of Endeavour Segment provide new insights into the low-temperature hydrothermal flow that continues long after crustal formation. Precipitation of alteration minerals due to fluid flow leads to changes in P-wave velocities within seismic Layer 2A (the uppermost layer of the oceanic crust) that vary markedly with extent of sediment blanketing the crust. In addition, intermediate-scale variations in the structure of Layers 2A and 2B with local topography are observed that may result from topographically driven fluid upflow and downflow on the ridge flanks.This research was supported by NSF OCE grants 0002488, 0002551, 0648303, 0648923, 0327872 and 0327885

Crustal thickness and Moho character of the fast-spreading East Pacific Rise from 9°42′N to 9°57′N from poststack-migrated 3-D MCS data

Author Posting. © American Geophysical Union, 2014. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 15 (2014): 634–657, doi:10.1002/2013GC005069.We computed crustal thickness (5740 ± 270 m) and mapped Moho reflection character using 3-D seismic data covering 658 km2 of the fast-spreading East Pacific Rise (EPR) from 9°42′N to 9°57′N. Moho reflections are imaged within ∼87% of the study area. Average crustal thickness varies little between large sections of the study area suggesting regionally uniform crustal production in the last ∼180 Ka. However, individual crustal thickness measurements differ by as much as 1.75 km indicating that the mantle melt delivery has not been uniform. Third-order, but not fourth-order ridge discontinuities are associated with changes in the Moho reflection character and/or near-axis crustal thickness. This suggests that the third-order segmentation is governed by melt distribution processes within the uppermost mantle while the fourth-order ridge segmentation arises from midcrustal to upper-crustal processes. In this light, we assign fourth-order ridge discontinuity status to the debated ridge segment boundary at ∼9°45′N and third-order status at ∼9°51.5′N to the ridge segment boundary previously interpreted as a fourth-order discontinuity. Our seismic results also suggest that the mechanism of lower-crustal accretion varies along the investigated section of the EPR but that the volume of melt delivered to the crust is mostly uniform. More efficient mantle melt extraction is inferred within the southern half of our survey area with greater proportion of the lower crust accreted from the axial magma lens than that for the northern half. This south-to-north variation in the crustal accretion style may be caused by interaction between the melt sources for the ridge and the Lamont seamounts.This research was supported by the National Science Foundation grants OCE0327872 to J. C. M., S. M. C., OCE327885 to J. P. C., OCE0624401 to M. R. N., and NSERC Discovery, CRC and CFI grants to M. R. N.2014-09-1