Molecular modeling of the Abeta1-42 peptide from Alzheimer's disease

The three-dimensional structure of the Alzheimer's disease Abeta1-42 peptide was predicted by sequence homology, threading approaches and by experimental observations. The Abeta molecule displayed a Greek key motif with four antiparallel beta-strands. To shield thermodynamically unfavorable domains, two Abeta molecules interact with each other to generate a beta-barrel structure with a hydrophilic surface and a hydrophobic core. The N-terminal domains of the dimer form crevices into which the non-polar C-termini are accommodated to yield a globular structure 27x32 A in diameter. Alternatively, the C-terminal domains of two opposing dimers could be extended to form an antiparallel beta- sheet. The stacking of these building blocks generates a helical protofilament. To create a thermodynamically more favorable structure, three protofilaments associate into a right-handed triple helix with a hydrophobic beta-sheet completely surrounded by the hydrophilic beta- barrels made of residues 1-28. Two triple helical strands can further associate into a right-handed amyloid filament. Although our model did not meet all the expected criteria, it nevertheless exhibited a series of naturally disposed structural features, revealed by other biophysical studies utilizing synthetic Abeta peptides. These characteristics are of functional significance in terms of Abeta- topology, fibril formation and cytotoxicity. The model also suggests that Abeta may not exist in a thermodynamically stable conformation, but rather as an ensemble of metastable dimeric structures some of which are capable of generating an extended C-terminal antiparallel beta-sheet essential in the promotion of fibrillogenesis.      

Identifying Small‐Molecule Binding Sites for Epigenetic Proteins at Domain–Domain Interfaces

Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well‐enclosed binding site amenable to small‐molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain–domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognising and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain–domain interfaces. For the tandem plant homeodomain–bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.     

Influence of the Mixed Propoxy/Ethoxy Spacer Arrangement Order and of the Ionic Head Group Nature on the Adsorption and Aggregation of Extended Surfactants

Two families of extended surfactants were prepared with the same head groups (carboxylate, sulfate, disodium phosphate) and different intermediate spacer structures. In one there was an average of 7 propylene oxide groups on the side of the tail and an average of 7 ethylene oxide groups on the side of the head, to produce a sequence of two different polarity segments. In the other case the spacer contained the same average numbers of propylene and ethylene oxide groups but in some homogeneous arrangement. The intermediate spacer structure, without ionic head group and in the cases of the carboxylate and sulfate extended surfactants, had a packing density reduction which is associated to the homogeneously alkoxide arrangement in the spacer. Such an arrangement was found to produce about 20% more surface area at the interface, apparently because it results in some plumpness due to the spacer folding to remain close to the interface. Both the critical micelle concentration and occupied interfacial area of the extended surfactant increased with the ionization of the anionic group associated with the electrostatic repulsion effect.     

Liquid crystals and living systems

Most lipids do not pass, on heating, directly from a crystalline structure to an isotropic structure. They are often characterized by a number of intermediate phases, ranging from the plastic crystal, where the center of gravity of the molecule may rotate about one or more axes while the three-dimensional order of the crystal remains, to nematic liquid crystals, which have birefrigent properties of crystals and yet are characterized by completely random ordering of the molecular centers. The smectic and cholesteric liquid crystalline structures are most commonly encountered in lipids. The structural characteristics of these systems are discussed. Of particular interest in living systems are liquid crystals, which are formed by cholesteric esters and many protein materials, and the two-dimensional crystals (smectic structure), which are formed by fatty acid derivatives. The mechanisms of energy transfer and the mechanical alignment in these liquid crystalline systems are unique and require different considerations from those found adaptable to liquids or solids. The properties of liquid crystals which might best be associated with living systems will be discussed, including surface properties and diffusivity.     

Oxide–Oxide Interfaces: Atomistic and Density Functional Study of Cubic-ZrO2 (100) ‖ NiO (111)

The cubic-ZrO₂ (100) ‖ NiO (111) interface provides an opportunity for comparison between atomic-scale measurements, atomistic simulations, and theoretical electronic structures. High-resolution electron microscopy indicates that the oxides share a common oxygen layer and that the small lattice strain is largely taken up by NiO near the interface. Using simple Coulomb plus Buckingham-type interatomic potentials, we are able to provide a more focused picture, revealing two types of boundary. The lowest energy interface is highly planar, almost ideal in structure; there is a second interface, of higher energy, that shows a rumpled structure with strain taken up by deformation of nickel chains. Depth profiling of atomic site energies permits calculation of interface versus bulk and surface energies, and it shows that the interface effects penetrate only two to three atomic layers. Embedded cluster density functional studies of bulk and interface-region sites permit the characterization of perturbations of electronic density around the boundaries.     

The construction of new proteins

Recent progresses in the elucidation of the folding mechanism and topology of proteins revealed that the formation of folding units with specific topological features is not restricted to a unique primary sequence. This finding presents the basis for the design of polypeptides having the propensity to fold into a tertiary structure that can be achieved by the assembly of peptide blocks exhibiting stable secondary structures. Conformational studies on model peptides show that Aib containing peptides with chain-lengths of 12-15 residues are able to form stable amphiphilic helices in solution. On the other hand, oligopeptides with alternating hydrophilic and hydrophobic residues are capable for β-structure formation for chain-lengths of 6-8 residues. Those amphiphilic secondary structures have been used as building-blocks for the design and synthesis of artificial folding units, their amphiphilic nature acting as major driving force for intramolecular folding. Spectroscopic data obtained for two polypeptides designed as βαβ-models actually suggest a folded conformation of these molecules in aqueous solution. The implications of these findings for the design of biologically active folded polypeptides are discussed.     

Phase behavior of an amphiphilic molecule in the presence of two solvents by dissipative particle dynamics

We examine the phase behavior of A_mB_n amphiphilic molecules in the presence of two solvents X₂ and Y₂, which are strongly selective for A and B, respectively, by dissipative particle dynamics (DPD). We find that increasing the immiscibility parameter between the two solvents not only drives a macrophase separation into two phases X₂-rich and Y₂-rich for systems at less concentrated regimes, but also expands the ordered microphase region at more concentrated regimes. It even induces a sequential transition of various ordered structures. This is not surprising since increasing the solvent immiscibility parameter enhances the preferentiality of X₂ for A and Y₂ for B, and thus qualitatively varies the degree of molecular asymmetry in the amphiphilic molecules. In general, our current results reveal that the DPD simulation method has successfully captured the phase separation behavior of an amphiphilic molecule in the presence of two solvents. However, we find that the packing order of the spherical micelles is greatly affected by the finite size of the simulation box. As such, it becomes difficult to examine the most stable packing array of spheres via the DPD method. Still, DPD reveals a possible spherical order of A15, which has been observed in some amphiphilic molecule systems.     

Dynamics of water interacting with interfaces, molecules, and ions

Water is a critical component of many chemical processes, in fields as diverse as biology and geology. Water in chemical, biological, and other systems frequently occurs in very crowded situations: the confined water must interact with a variety of interfaces and molecular groups, often on a characteristic length scale of nanometers. Water's behavior in diverse environments is an important contributor to the functioning of chemical systems. In biology, water is found in cells, where it hydrates membranes and large biomolecules. In geology, interfacial water molecules can control ion adsorption and mineral dissolution. Embedded water molecules can change the structure of zeolites. In chemistry, water is an important polar solvent that is often in contact with interfaces, for example, in ion-exchange resin systems. Water is a very small molecule; its unusual properties for its size are attributable to the formation of extended hydrogen bond networks. A water molecule is similar in mass and volume to methane, but methane is a gas at room temperature, with melting and boiling points of 91 and 112 K, respectively. This is in contrast to water, with melting and boiling points of 273 and 373 K, respectively. The difference is that water forms up to four hydrogen bonds with approximately tetrahedral geometry. Water's hydrogen bond network is not static. Hydrogen bonds are constantly forming and breaking. In bulk water, the time scale for hydrogen bond randomization through concerted formation and dissociation of hydrogen bonds is approximately 2 ps. Water's rapid hydrogen bond rearrangement makes possible many of the processes that occur in water, such as protein folding and ion solvation. However, many processes involving water do not take place in pure bulk water, and water's hydrogen bond structural dynamics can be substantially influenced by the presence of, for example, interfaces, ions, and large molecules. In this Account, spectroscopic studies that have been used to explore the details of these influences are discussed. Because rearrangements of water molecules occur so quickly, ultrafast infrared experiments that probe water's hydroxyl stretching mode are useful in providing direct information about water dynamics on the appropriate time scales. Infrared polarization-selective pump-probe experiments and two-dimensional infrared (2D IR) vibrational echo experiments have been used to study the hydrogen bond dynamics of water. Water orientational relaxation, which requires hydrogen bond rearrangements, has been studied at spherical interfaces of ionic reverse micelles and compared with planar interfaces of lamellar structures composed of the same surfactants. Water orientational relaxation slows considerably at interfaces. It is found that the geometry of the interface is less important than the presence of the interface. The influence of ions is shown to slow hydrogen bond rearrangements. However, comparing an ionic interface to a neutral interface demonstrates that the chemical nature of the interface is less important than the presence of the interface. Finally, it is found that the dynamics of water at an organic interface is very similar to water molecules interacting with a large polyether.     

两亲性海藻多糖在乳化和分散中应用的研究进展

海藻多糖是一种天然的凝胶多糖，其分子链上原生的亲水、疏水基团赋予其天然的两亲性，能够在一定程度上改善非均相之间的界面相容性，具有天然凝胶网络结构的海藻多糖还可在溶胶体系中有效阻止分散相之间的再聚集，因而海藻多糖在乳化及分散中具有极佳的应用潜能。本文介绍了海藻酸盐、岩藻多糖、卡拉胶、琼脂、石莼多糖等常见海藻多糖的化学组成、结构与性质, 并从其糖基单元上的羧基、硫酸酯基等亲水基团与甲氧基、乙酰基、蛋白质等疏水基团构成的两亲性结构出发，总结了两亲性结构对海藻多糖分子构型、表面活性及流变性质的影响，进而综述海藻多糖两亲性结构在乳化和分散中的应用。同时，还总结了通过物理或化学手段增强海藻多糖两亲性能的相关研究，例如带电疏水粒子的静电耦合、长碳链疏水化合物的化学接枝等，介绍了衍生化海藻多糖在乳化和分散中应用的研究进展，并对海藻多糖界面吸附活性增强的方向进行了展望。     

Anodic etching of InP using neutral NaCl electrolyte

We present porous InP formation in neutral NaCl solution. N-type InP wafers were etched at linear sweep voltammetry and at constant potential, respectively. The results showed that the potential 7.0–8.5 V is suitable for forming the regular pores of InP. The reaction that the eight holes are used to dissolve one InP molecule was confirmed by our experimental results. The crystallographically oriented pores of InP formed were suggested to be the synergic effect between surface state and effect of the surface curvature. The current-line oriented pores formed were ascribed to the effect of surface curvature.     

Synthesis and Properties of Dicephalic Cationic Surfactants Containing a Quaternary Ammonium and a Guanidine Group

Novel dicephalic surfactants containing a quaternary ammonium and a guanidine group were synthesized, and the effect of the alkyl chain length on micellization and antimicrobial activity were investigated. Surface tension and conductivity were applied to study the self-aggregation of the amphiphilic molecule in aqueous solution. The results indicated that these compounds reduce the surface tension to a level of 30–36 mN/m at the air/water interface and that there is a characteristic chain length dependence of the micellization process of surfactants. The antimicrobial activity was evaluated against Gram-negative, Gram-positive bacteria and fungi, indicating strong antibacterial activity against tested strains.     

Wettability and microstructure of polymer surfaces: stereochemical and conformational aspects

Stereoregular poly(methyl methacrylates) (PMMAs) solvent-cast in the form of films against a glass substrate were employed as model systems for a systematic study of the relationship between the molecular structure (as characterized by the stereochemistry and conformations of macromolecules), the functional-group composition, and the wettability of polymer surfaces. The water wettability of a syndiotactic surface was found to be highly sensitive to the polarity of the adjacent phase in the film-casting process, whereas the wettability of an isotactic surface was invariant to the polarity of the contacting medium. The tacticity-dependent wetting behavior arises from the difference in the extent of functional-group surface segregation or, in other words, from the different surface activity of the different tactic versions of the polymer. This difference, in turn, is associated with fundamental distinctions in the conformational structures energetically allowed for the isotactic and syndiotactic configurations of the polymer chain; the syndiotactic macromolecule is capable of adopting an amphiphilic surface conformation, whereas the energetically allowed conformational structures of the isotactic macromolecule do not possess amphiphilic character. In view of these findings, the isotactic surfaces can be regarded as 'ideal' model surfaces for research on the fundamentals of wetting phenomena. In addition, there is evidence for failure of the basic assumption of the Cassie approach, i.e. the assumption of macroscopic chemical heterogeneity, to describe adequately the wetting behavior of isotactic PMMA surfaces.     

Nanographenes as active components of single-molecule electronics and how a scanning tunneling microscope puts them to work

Single-molecule electronics, that is, realizing novel electronic functionalities from single (or very few) molecules, holds promise for application in various technologies, including signal processing and sensing. Nanographenes, which are extended polycyclic aromatic hydrocarbons (PAHs), are highly attractive subjects for studies of single-molecule electronics because the electronic properties of their flat conjugated systems can be varied dramatically through synthetic modification of their sizes and topologies. Single nanographenes provide high tunneling currents when adsorbed flat onto conducting substrates, such as graphite. Because of their chemical inertness, nanographenes interact only weakly with these substrates, thereby preventing the need for special epitaxial structure matching. Instead, self-assembly at the interface between a conducting solid, such as the basal plane of graphite, and a nanographene solution generally leads to highly ordered monolayers. Scanning tunneling spectroscopy (STS) allows the current-voltage characteristics to be measured through a single molecule positioned between two electrodes; the key to the success of STS is the ability to position the scanning tunneling microscopy (STM) tip freely with respect to the molecule in all dimensions, that is, both parallel and perpendicular to the surface. In this Account, we report the properties of nanographenes having sizes ranging from 0.7 to 3.1 nm and exhibiting various symmetry, periphery, and substitution types. The size of the aromatic system and the nature of its perimeter are two essential features affecting its HOMO-LUMO gap and charge carrier mobility in the condensed phase. Moreover, the extended pi area of larger substituted PAHs improves the degree of self-ordering, another key requirement for high-performance electronic devices. Self-assembly at the interface between an organic solution and the basal plane of graphite allows deposition of single molecules within the well-defined environment of a molecular monolayer. We have used STM and STS to investigate both the structures and electronic properties of these single molecules in situ. Indeed, we have observed key electronic functions, rectification and current control through single molecules, within a prototypical chemical field-effect transistor at ambient temperature. The combination of nanographenes and STM/STS, with the PAHs self-assembled in oriented molecular mono- or bilayers at the interface between an organic solution and the basal plane of graphite and contacted by the STM tip, is a simple, reliable, and versatile system for developing the fundamental concepts of molecular electronics. Our future targets include fast reversible molecular switches and complex molecular electronic devices coupled together from several single-molecule systems.     

An immersion calorimetry study of the interaction of organic compounds with carbon nanotube surfaces

The interaction of organic chemicals with the surface of carbon nanotubes (CNTs) has been studied by immersion calorimetry revealing new information about the unique CNT surface structures. The curvature of the graphene sheets of in the CNTs increases the adsorption strength of aromatic compounds compared to flat graphite surfaces. For a given CNT, the adsorption affinity of a non-polar aromatic molecule correlated poorly with the CNT hydrophobicity. Comparison of the immersion enthalpies that evolved when the solids were immersed in organic chemicals reveals the formation of π–π stacking interactions, H-bonds or electron–accepting interactions depending on the CNT surfaces and on the immersion substrate. The number of oxygen groups on CNTs seems to modify the electron density of their surfaces and therefore the interaction mechanism with the adsorbates.     

A stochastic analysis of the flow of two immiscible fluids in porous media: The case when the viscosities of the fluids are equal

A new stochastic theory is developed to explain the flow of two immiscible fluids in porous medium when the viscosity difference between two fluids is zero. In an individual micropore the radius of curvature of the interface separating the fluids is assumed constant and flow is modeled by the random jumping of microscopic interfaces. A one dimensional model composed of an array of parallel capillary tubes of constant radius is analyzed in detail. For the case in which two fluids have equal viscosity an analytical solution is obtained. The fluid displacement process is Fickian and dispersion is described in terms of a diffusion or spreading constant.     

Impact of thickness on CO2 concentration profiles within polymer films swollen near the critical pressure

The isothermal swelling of polymer thin films by a supercritical fluid does not increase monotonically with increasing chemical potential (pressure), but rather a maximum in swelling is generally observed near the critical pressure. A reactive templating approach utilizing the condensation of silica within hydrophilic domains of a swollen amphiphilic polymer film enables visualization of the qualitative concentration profile of CO₂ by the changes in the size of hydrophobic domains (pores) with cross sectional TEM microscopy; specifically, isothermal swelling of poly(ethylene oxide-propylene oxide-ethylene oxide) films by CO₂ at 60 °C is examined. Films that contain thickness gradients are used to avoid any uncertainties in the impact of thickness due to variations in the temperature or pressure during the silica modification. A uniform pore size (local swelling) is observed for all film thicknesses when the pressure is outside of the anomalous maximum in the film swelling, except for a small increase at the buried interface due to preferential adsorption of CO₂ to the native silicon oxide surface of the substrate. However at this swelling maximum, a gradient in the pore size is observed at both interfaces. These swelling gradients at interfaces appear to be responsible for the anomalous maximum in thin films. As the film thickness increases beyond 350 nm, there is a decrease in the maximum swelling at the free interface.     

Disrupting the hydrophobic patches at the antibody variable/constant domain interface: improved in vivo folding and physical characterization of an engineered scFv fragment

By constructing Fv and single-chain Fv (scFv) fragments of antibodies, the variable domains are taken out of their natural context in the Fab fragment, where they are associated with the constant domains of the light (CL) and heavy chain (CH1). As a consequence, all residues of the former variable/constant domain interface become solvent exposed. In an analysis of 30 non-redundant Fab structures it was found that at the former variable/constant domain interface of the Fv fragment the frequency of exposed hydrophobic residues is much higher than in the rest of the Fv fragment surface. We investigated the importance of these residues for different properties such as folding in vivo and in vitro, thermodynamic stability, solubility of the native protein and antigen affinity. The experimental model system was the scFv fragment of the anti-fluorescein antibody 4-4-20, of which only 2% is native when expressed in the periplasm of Escherichia coli. To improve its in vivo folding, a mutagenesis study of three newly exposed interfacial residues in various combinations was carried out. The replacement of one of the residues (V84D in VH) led to a 25-fold increase of the functional periplasmic expression yield of the scFv fragment of the antibody 4-4-20. With the purified scFv fragment it was shown that the thermodynamic stability and the antigen binding constant are not influenced by these mutations, but the rate of the thermally induced aggregation reaction is decreased. Only a minor effect on the solubility of the native protein was observed, demonstrating that the mutations prevent aggregation during folding and not of the native protein. Since the construction of all scFv fragments leads to the exposure of these residues at the former variable/constant domain interface, this strategy should be generally applicable for improving the in vivo folding of scFv fragments and, by analogy, also the in vivo folding of other engineered protein domains.      

Amphiphilic Copolymers PDMAEMAm-b-PAAn and Their Complexes with Surfactants at the Air/Water Interface

The properties of amphiphilic copolymers (poly(2-(dimethylamino)ethyl methacrylate)-block-poly(acrylic acid), PDMAEMA_m-b-PAA_n) and their complexes with a traditional surfactant (dimethyldioctadecylammonium bromide) and a novel Gemini surfactant, (propanediyl-bis(dimethyloctadecylammonium bromide) ([C₁₈H₃₇(CH₃)₂N⁺-(CH₂)₃-N⁺(CH₃)₂ C₁₈H₃₇]·2Br⁻, 18-3-18), at the air/water interface were investigated. Surface tension and surface pressure were used to monitor the surface behavior of these systems, and atomic force microscopy was used to visualize the morphology of the corresponding Langmuir–Blodgett film. PDMAEMA_m-b-PAA_n can form surface micelles at the air/water interface and the addition of surfactants can significantly influence the structure of the complex film due to electrostatic interaction and hydrophobic interaction. In particular, the spacer in a Gemini surfactant can act as a bridge to connect different PDMAEMA₇₀-b-PAA₆₀ micelles, which is favorable for the formation of a necklace-like structure. This originates from that one head group can interact with a PDMAEMA₇₀-b-PAA₆₀ molecule, and the other head group can interact with another PDMAEMA₇₀-b-PAA₆₀ molecule, which might belong to different micelles. The results suggest that the special interfacial structures and performances of Gemini/PDMAEMA-b-PAA complexes are caused by the unique molecular structures of the Gemini surfactant.