Aggregation state and neurotoxic properties of alzheimer β-amyloid peptide

Alzheimer's disease (AD) represents the most common form of senile dementia and represents a tremendous health problem as the world population is aging. AD is characterized by the accumulation of amyloid β-peptide (Aβ) in the brain and the loss of cholinergic neurons in the basal forebrain. Accumulation of soluble and insoluble assemblies of Aβ in the brain is a crucial event in AD pathogenesis and the presence of amyloid plaques in the brain is required for definitive identification of AD. Yet, there is no correlation between amyloid plaques and the degree of dementia. In the past two decades researchers have devoted their effort to study and explain the mechanisms involved in the pathology of this devastating disease. Studies from different areas of the natural and medical sciences have provided important information towards the elucidation of some of the pathological processes that take place in AD. An aspect of crucial importance is the aggregation state of Aβ peptide and its role in neuropathology. Here, we discuss recent studies aimed at the identification of Aβ protein aggregates, the characterization of their toxic potential and the development of therapeutic strategies that target Aβ aggregation.     

Characterization of self-assembled monolayers of thiols on Au(111)

Self-assembled monolayers (SAMs) of n-butanethiol, n-dodecanethiol and their equimolar mixture on Au(111) were prepared and characterized by ellipsometry, contact angle measurement, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). Results revealed that these SAMs are oriented ultrathin films with the thickness of nanometer scale, and the SAMs were influenced by the molecular chain length, the lattice orientation and cleanliness of the substrates. The surface of the longer chain SAM is hydrophobic. The thicknesses of three SAMs of n-butanethiol, n-dodecanethiol and their mixture revealed by ellipsometry and XPS are about 0.59 - 0.67nm, 1.60- 1.69 nm and 1.23 - 1.32nm, respectively. AFM images further demonstrated that the SAM formed by the mixture has some microdomains with two different thicknesses.     

Molecular recognition of a self-assembled monolayer of a polydithiocarbamate derivative of β-cyclodextrin on silver

The synthesis and molecular recognition properties of a new sulfur containing β-cyclodextrin (β-CD) derivative chemisorbed on a silver surface are described. Hepta-6-amino-6-deoxy-β-CD was allowed to react with CS₂ in the presence of ammonia to give a mixture of partially substituted dithiocarbamate derivatives with an average degree of substitution of 4.5. A modified silver electrode with this derivative is capable of discriminating between the three positional isomers of nitrobenzoate ion and nitrophenol, as determined by cyclic voltammetry. Only the meta- and para-isomers give a signal corresponding to the reduction of the nitro group. This is attributed to the different orientations of the nitro group with respect to the silver surface after inclusion in the CD cavity. Experiments in the presence of cyclohexanol showed a decrease in signal intensity of the meta- and para-isomers which is associated with the competitive complexation of this guest, suggesting that the electroactive probe is complexed to the cavity.     

Simulations of nanocylinders self-assembled from cyclic β-tripeptides

This paper examines the self-assembly of cyclic β-tripeptides using density functional theory. On the basis of literature precedents, these cyclic peptides were expected to self-assemble into cylindrical structures by stacking through backbone-backbone hydrogen bonding. Our calculations show that such stacking is energetically favorable, that the association energy per cyclic peptide decreases (becomes more favorable), and that the overall macrodipole moment of the cylindrical assembly increases with the number of stacked rings, for up to eight rings. For a structure in which two peptide ring units are joined through a single side chain-side chain covalent linker, the association energy between the two rings is favorable, albeit less so than for the unlinked rings. Significantly, the association energy in the dimers is only weakly dependent on the length (above a certain minimum) and conformation of the covalent linkers. Finally, as a plausible route for controlling assembly/disassembly of nanocylinders, we show that, for a pair of rings, each bearing a single amino-functionalized side chain, protonation of the amino group results in a strongly positive (unfavorable) association energy between the two rings.     

Molecular dynamics simulations on [FePAH]+ π-complexes of astrophysical interest: anharmonic infrared spectroscopy

In this article, classical Born-Oppenheimer molecular dynamics (MD) simulations in the microcanonical ensemble are performed on neutral and cationic polycyclic aromatic hydrocarbon (PAH) species, focusing on [FePAH](+)π-complexes. Their anharmonic mid-infrared (mid-IR) spectra in the classical approximation are derived. This approach allows us to describe the influence of the energy of a system on its IR spectrum in terms of band-shifts and broadenings. The MD simulations are performed on a potential energy surface (PES) described at the self-consistent-charge density functional tight-binding level of theory. The PES is benchmarked on DFT calculations, showing the validity of the approach for complexes of Fe(+) with PAHs larger than coronene (C(24)H(12)) that are of astrophysical interest. MD simulations at high temperature show the occurrence of the diffusion of the Fe cation on the surface of the PAH. It proceeds through the edge of the carbon skeleton which is the lowest energy pathway presenting barriers smaller than 1 eV. Although only qualitative information on the band broadenings can be obtained, we show that the dependence of the computed positions of the main bands of [C(24)H(12)](0/+)and [FeC(24)H(12)](+)π-complexes on temperature can be fit by linear laws. The spectral trends determined for [FeC(24)H(12)](+) are compared to those of N-substituted [C(23)NH(12)](+)and [SiC(24)H(12)](+)π-complexes of astrophysical interest.     

Molecular dynamics studies of the inhibitory mechanism of copper（Ⅱ） on aggregation of amyloid β-peptide

The inhibitory mechanism of copper（Ⅱ） on the aggegation of amyloid β-peptide （Aβ） was investigated by molecular dynamics simulations. The binding mode ofcopper（Ⅱ） with Aβ is characterized by the imidazole nitrogen atom, Nπ, of the histidine residue H 13, acting as the anchoring site, and the backbone＇s deprotoned amide nitogen atoms as the main binding sites. Drove by the coordination bonds and their induced hydrogen bond net, the conformations of Aβ converted from β-sheet non-β-sheet conformations, which destabilized the aggregation of Aβ into fibrils.     

Behavior of β-amyloid 1-16 at the air-water interface at varying pH by nonlinear spectroscopy and molecular dynamics simulations

The adsorption and aggregation of β-amyloid (1-16) fragment at the air-water interface was investigated by the combination of second harmonic generation (SHG) spectroscopy, Brewster angle microscopy (BAM), and molecular dynamics simulations (MD). The Gibbs free energy of surface adsorption was measured to be -10.3 kcal/mol for bulk pHs of 7.4 and 3, but no adsorption was observed for pH 10-11. The 1-16 fragment is believed not to be involved in fibril formation of the β-amyloid protein, but it exhibits interesting behavior at the air-water interface, as manifested in two time scales for the observed SHG response. The shorter time scale (minutes) reflects the surface adsorption, and the longer time scale (hours) reflects rearrangement and aggregation of the peptide at the air-water interface. Both of these processes are also evidenced by BAM measurements. MD simulations confirm the pH dependence of surface behavior of the β-amyloid, with largest surface affinity found at pH = 7. It also follows from the simulations that phenylalanine is the most surface exposed residue, followed by tyrosine and histidine in their neutral form.     

Molecular dynamics simulation study on zwitterionic structure to maintain the normal conformations of Glutathione

Molecular dynamics simulations were applied to normal conformational Glutathione (GSH) and GSH over zwitterionic and hydrophobic surfaces respectively. Conformational analysis of GSH during the simulation time on RMSD, conformational flexibility and dihedral distribution were performed. The re- sults showed that zwitterionic structure maintains the normal conformations of GSH to a better extent, which should be a first good proof of the hypothesis of "maintain of normal structure".     

Molecular Simulation Study of Alkyl monolayers on Si(Ⅲ） Surface

The structure of eight-carbon monolayers on the H-terminated Si(Ⅲ） surface was investigated by molecular simulation method.The best substitution percent 50% for octene or octyne-derived monolayer can be obtained using molecular mechanics calculation.And the densely packed,well-ordered monolayer on Si(Ⅲ） surfacec and be shown through energy minimization in the suitable-size simulation cell.     

Stereoselective inclusion mechanism of ketoprofen into β-cyclodextrin: insights from molecular dynamics simulations and free energy calculations

The host–guest inclusion mechanism formed between β-cyclodextrin and those poorly water-soluble drug molecules has important applications in supramolecular chemistry, biology and pharmacy. In this work, the chiral recognition ability of β-cyclodextrin to one of nonsteroidal anti-inflammatory drugs, ketoprofen, has been systematically investigated using molecular dynamics and free energy simulation methods. The R- and S-enantiomers of ketoprofen were explicitly bound within the cyclodextrin cavity in our simulations, respectively. In consistent with experimental observations, tiny structural difference between two isomers could be observed. Calculated absolute binding free energies using adapted biasing force (ABF) method and MM/GBSA approach for both isomers are comparable to experimental values. Significant binding fluctuations along the MD trajectory have been observed. The free energy profiles calculated using two different approaches reveal that the ketoprofen prefers binding in the cavity with the carboxylate group facing the wider edge of β-cyclodextrin. Similar free energy profiles for two enantiomers obtained using ABF calculations indicate that it is very hard to separate and identify the chiral conjugates within the framework of the natural β-cyclodextrin.     

Polypyrrole on self-assembled monolayers of a pyrrolyl lipoic acid derivative—electrosynthesis and polymer film characterization

The electropolymerization of pyrrole on gold modified by a self-assembled monolayer (SAM) of a pyrrolyl lipoic acid derivative was investigated in detail and the results compared to those obtained on bare substrates. Both under potentiostatic and potentiodynamic control, a slight blocking action of the underlying SAM could be observed for the initial stages of polymer growth but thereafter the electrochemical features were similar to those collected for polypyrrole (PPy) deposition on bare gold. The morphology and structure of PPy films formed on the SAMs were characterized by atomic force microscopy and X-ray diffraction, which revealed that those polymer properties are much more influenced by the electrochemical mode of preparation, than by the underlying SAMs. While, when compared to PPy on bare gold, no effect has been detected on thin layers deposited at constant potential, surface areas with rather irregular morphology, as well as a small but beneficial influence in inducing order on the first few layers of the polymer film, have been observed on similar films formed by cyclic voltammetry. The typical globular morphology of PPy has always been observed for relatively thick layers in which the redox behavior, analyzed by in situ AFM, showed an increase in volume of the polymer nodules upon reduction, largely due to the SAM reorganization induced by the applied potential.     

Molecular simulation of alkyl monolayers on the Si(111) surface YUAN

The preparation of monolayers on silicon surface is of growing interest for potential applica-tions in biosensor or semiconductor technology[1—5]. The alkyl modified Si(111) surfaces[6—10] can be obtained using the thermal, catalyzed, or photochemical reaction of hydrogen-terminated sili-con with alkenes, Grignard reagents, and so on. At the same time, the monolayer properties on Si(111) surface have been studied by a variety of experimental methods[8—10] such as X-ray photo-electron spect…     

Molecular dynamics simulations on the structures and properties of ε-CL-20-based PBXs ——Primary theoretical studies on HEDM formulation design

Five polymer bonded explosives (PBXs) with the base explosive ε-CL-20 (hexanitrohexaazaisowurtzi- tane), the most important high energy density compound (HEDC), and five polymer binders (Estane 5703, GAP, HTPB, PEG, and F2314) were constructed. Molecular dynamics (MD) method was employed to investigate their binding energies (Ebind), compatibility, safety, mechanical properties, and energetic properties. The information and rules were reported for choosing better binders and guiding formula- tion design of high energy density material (HEDM). According to the calculated binding energies, the ordering of compatibility and stability of the five PBXs was predicted as ε-CL-20/PEG > ε-CL-20/ Estane5703 ≈ε-CL-20/GAP > ε-CL-20/HTPB > ε-CL-20/F2314. By pair correlation function g(r) analyses, hydrogen bonds and vdw are found to be the main interactions between the two components. The elasticity and isotropy of PBXs based ε-CL-20 can be obviously improved more than pure ε-CL-20 crystal. It is not by changing the molecular structures of ε-CL-20 for each binder to affect the sensitivity. The safety and energetic properties of these PBXs are mainly influenced by the thermal capability (C°p) and density (ρ) of binders, respectively.     

Molecular dynamics simulations on the structures and properties of ε-CL-20-based PBXs——Primary theoretical studies on HEDM formulation design

Five polymer bonded explosives (PBXs) with the base explosiveε-CL-20 (hexanitrohexaazaisowurtzitane), the most important high energy density compound (HEDC), and five polymer binders (Estane 5703, GAP, HTPB, PEG, and F2314) were constructed. Molecular dynamics (MD) method was employed to investigate their binding energies (Ebind), compatibility, safety, mechanical properties, and energetic properties. The information and rules were reported for choosing better binders and guiding formulation design of high energy density material (HEDM). According to the calculated binding energies, the ordering of compatibility and stability of the five PBXs was predicted as ε-CL-20/PEG ＞ ε-CL-20/ Estane5703 ≈ε-CL-20/GAP ＞ ε-CL-20/HTPB ＞ ε-CL-20/F2314. By pair correlation function g(r) analyses, hydrogen bonds and vdw are found to be the main interactions between the two components. The elasticity and isotropy of PBXs based ε-CL-20 can be obviously improved more than pure ε-CL-20 crystal. It is not by changing the molecular structures of ε-CL-20 for each binder to affect the sensitivity. The safety and energetic properties of these PBXs are mainly influenced by the thermal capability (C°p) and density (ρ) of binders, respectively.     

Formation of self-assembled monolayers of π-conjugated molecules on TiO2 surfaces by thermal grafting of aryl and benzyl halides

We demonstrate the formation of molecular monolayers of π-conjugated organic molecules on nanocrystalline TiO(2) surfaces through the thermal grafting of benzyl and aryl halides. X-ray photoelectron spectroscopy and Fourier-transform infrared spectroscopy were used to characterize the reactivity of aryl and benzyl chlorides, bromides, and iodides with TiO(2) surfaces, along with controls consisting of nonhalogenated compounds. Our results show that benzyl and aryl halides follow a similar reactivity trend (I > Br > Cl > H). While the ability to graft benzyl halides is consistent with the well-known Williamson ether synthesis, the grafting of aryl halides has no similar precedent. The unique reactivity of the TiO(2) surface is demonstrated using nuclear magnetic resonance spectroscopy to compare the surface reactions with the liquid-phase interactions of benzyl and aryl iodides with tert-butanol and -butoxide anion. While the aryl iodides show no detectable reactivity with a tert-butanol/tert-butoxide mixture, they react with TiO(2) within 2 h at 50 °C. Atomic force microscopy studies show that grafting of 4-iodo-1-(trifluoromethyl)benzene onto the rutile TiO(2)(110) surface leads to a very uniform, homogeneous molecular layer with a thickness of ～0.45 nm, demonstrating formation of a self-terminating molecular monolayer. Thermal grafting of aryl iodides provides a facile route to link π-conjugated molecules to TiO(2) surfaces with the shortest possible linkage between the conjugated electron system and the TiO(2).     

Structural evolution of Iowa mutant β-amyloid fibrils from polymorphic to homogeneous states under repeated seeded growth

Structural variations in β-amyloid fibrils are potentially important to the toxicity of these fibrils in Alzheimer's disease (AD). We describe a repeated seeding protocol that selects a homogeneous fibril structure from a polymorphic initial state in the case of 40-residue β-amyloid fibrils with the Asp23-to-Asn, or Iowa, mutation (D23N-Aβ(1-40)). We use thioflavin T (ThT) fluorescence, transmission electron microscopy (TEM), and solid-state nuclear magnetic resonance (NMR) to track the evolution of fibril structure through multiple generations under this protocol. The data show that (i) repeated seeding selectively amplifies a single D23N-Aβ(1-40) fibril structure that can be a minor component of the initial polymorphic state; (ii) the final structure is highly sensitive to growth conditions, including pH, temperature, and agitation; (iii) although the initial state can include fibrils that contain both antiparallel and parallel β-sheets, the final structures contain only parallel β-sheets, suggesting that antiparallel β-sheet structures are thermodynamically and kinetically metastable. Additionally, our data demonstrate that ThT fluorescence enhancements, which are commonly used to monitor amyloid fibril formation, vary strongly with structural variations, even among fibrils comprised of the same polypeptide. Finally, we present a simple mathematical model that describes the structural evolution of fibril samples under repeated seeding.     

Domain motion of individual F1-ATPase β-subunits during unbiased molecular dynamics simulations

F(1)-ATPase is the catalytic domain of F(1)F(o)-ATP synthase and consists of a hexameric arrangement of three noncatalytic α and three catalytic β subunits. We have used unbiased molecular dynamics simulations with a total simulation time of 900 ns to investigate the dynamic relaxation properties of isolated β-subunits as a step toward explaining the function of the integral F(1) unit. To this end, we simulated the open (β(E)) and the closed (β(TP)) conformations under unbiased conditions for up to 120 ns each using several samples. The simulations confirm that nucleotide-free β(E) retains its open configuration over the course of the simulations. The same is true when the neighboring α subunits are included. The nucleotide-depleted as well as the nucleotide-bound isolated β(TP) subunits show a significant trend toward the open conformation during our simulations, with one trajectory per case opening completely. Hence, our simulations suggest that the equilibrium conformation of a nucleotide-free β-subunit is the open conformation and that the transition from the closed to the open conformation can occur on a time scale of a few tens of nanoseconds.     

Standing up versus looping over: controlling the geometry of self-assembled monolayers of α,ω-diynes on gold

It is shown that self-assembled monolayers (SAMs) composed of α,ω-diynes on gold have different structures depending on the concentration of molecules used to make the SAM. Evidence for both hairpinned and standing-up molecules is provided. This behavior is in contrast to SAMs of α,ω-dithiols on gold, which generally form SAMs with only the straight conformation. The looped SAMs composed of α,ω-diynes offer a less densely packed and thus somewhat accessible surface that may be useful when the underlying surface is used as an electrode. Furthermore, biasing the structure of the molecules in the SAM between looped and standing-up may be useful in the design of dynamic surfaces.     

Unusual aggregates from the oxidation of alkene self-assembled monolayers: a previously unrecognized mechanism for SAM ozonolysis?

Self-assembled monolayers (SAMs) of vinyl-terminated 3- and 8-carbon compounds were generated on Si substrates and reacted at room temperature with approximately 1 ppm gaseous O(3). A combination of atomic force microscopy (AFM), scanning electron microscopy (SEM), Auger electron spectroscopy (AES) and time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used to study the surface composition and morphology after oxidation. A distribution of large ( approximately 0.1-10 microm) organic aggregates was formed, while the surrounding substrate became depleted of carbon compared to the unreacted SAM. This highly unusual result establishes that the mechanism of ozonolysis of alkene SAMs must have a channel that is unique compared to that in the gas phase or in solution, and may involve polymerization induced by the Criegee intermediate (CI). Oxidation at 60% RH led to the formation of a number of smaller aggregates, suggesting water intercepted the CI in competition with aggregate formation. The uptake of water, measured using transmission FTIR, was not increased upon oxidation of these films. In conjunction with literature reports of polymer formation from VOC-NO(x) photooxidations, these results suggest that formation of aggregates and polymers in the atmosphere is much more widespread than previously thought. The implications for the ozonolysis of alkenes on surfaces, for the transformation of organics in the atmosphere, and for the reactions and stability of unsaturated SAMs, are discussed.