Filling-in Void and Sparse Regions in Protein Sequence Space by Protein-Like Artificial Sequences Enables Remarkable Enhancement in Remote Homology Detection Capability

Protein functional annotation relies on the identification of accurate relationships, sequence divergence being a key factor. This is especially evident when distant protein relationships are demonstrated only with three-dimensional structures. To address this challenge, we describe a computational approach to purposefully bridge gaps between related protein families through directed design of protein-like ``linker'' sequences. For this, we represented SCOP domain families, integrated with sequence homologues, as multiple profiles and performed HMM-HMM alignments between related domain families. Where convincing alignments were achieved, we applied a roulette wheel-based method to design 3,611,010 protein-like sequences corresponding to 374 SCOP folds. To analyze their ability to link proteins in homology searches, we used 3024 queries to search two databases, one containing only natural sequences and another one additionally containing designed sequences. Our results showed that augmented database searches showed up to 30% improvement in fold coverage for over 74% of the folds, with 52 folds achieving all theoretically possible connections. Although sequences could not be designed between some families, the availability of designed sequences between other families within the fold established the sequence continuum to demonstrate 373 difficult relationships. Ultimately, as a practical and realistic extension, we demonstrate that such protein-like sequences can be ``plugged-into'' routine and generic sequence database searches to empower not only remote homology detection but also fold recognition. Our richly statistically supported findings show that complementary searches in both databases will increase the effectiveness of sequence-based searches in recognizing all homologues sharing a common fold. (C) 2013 Elsevier Ltd. All rights reserved.

Microspherical, hierarchical structures of blue-green-emitting Dy:GdOOH and Dy:Gd2O3

Dy-doped GdOOH microspherical structures were prepared in minutes without using any structure-directing agents, through the microwave irradiation route. The as-prepared product consists of nearly monodisperse sphere-like entities with each one representing a three-level hierarchy in its formation. Dy:GdOOH powder samples show a bright blue-green luminescence under UV excitation, making these structures potentially important in the field of optical and luminescent devices. Finally, thermal conversion to the corresponding oxide structures occurs at modest temperatures, spherical morphology intact and with enhanced luminescence behaviour. (C) 2014 Elsevier B.V. All rights reserved.

INDUCTION OF FOLDED STRUCTURES IN DESIGNED PEPTIDES USING CONFORMATIONALLY CONSTRAINED RESIDUES

Folding into compact globular structures, with well-defined modules of secondary structure, appears to be a characteristic of long polypeptide chains, with a specific patterning of coded amino acid residues along the length of sequence. Cooperative hydrogen bond driven secondary structure formation and solvent forces, which contribute favorably to the entropy of folding, by promoting compaction of the polymeric chain, have long been discussed as major determinants of the folding process. First principles design approaches, which use non-coded amino acids, employ an alternative structure directing strategy, by using amino acid residues which exhibit a strong conformational bias for specific regions of the Ramachandran map. This overview of ongoing studies in the authors' laboratory, attempts to explore the use of conformationally restricted amino acid residues in the design of peptides with well-defined secondary structures. Short peptides composed of 20 genetically coded amino acids usually exist in solution as an ensemble of equilibrating conformations. Apolar peptide sequences, which are readily soluble in organic solvents like chloroform and methanol, facilitate formation of structures which are predominately driven by intramolecular hydrogen bond formation. The choice of sequences containing residues with a limited range of conformational choices strongly favors formation of local turn structures, stabilized by short range intramolecular hydrogen bonds. Two residue beta-turns can nucleate either helical or hairpin folding, depending on the precise conformation of the turn segment Restriction of the conformational space available to amino acid residues is easily achieved by introduction of an additional alkyl group at the C alpha carbon atom or by side chain backbone cyclization, as in proline. Studies of synthetic sequences incorporating two prototype residues alpha-aminoisobutyric acid (Aib) and D-proline (DPro) illustrate the utility of the strategy in construction of helices and hairpins. Extensions to the design of conformationally switchable sequences and structurally defined hybrid peptides containing backbone homologated residues are also surveyed.

Polymorphic phase transition among the titania crystal structures using a solution-based approach: from precursor chemistry to nucleation process

Nanocrystalline titania are a robust candidate for various functional applications owing to its non-toxicity, cheap availability, ease of preparation and exceptional photochemical as well as thermal stability. The uniqueness in each lattice structure of titania leads to multifaceted physico-chemical and opto-electronic properties, which yield different functionalities and thus influence their performances in various green energy applications. The high temperature treatment for crystallizing titania triggers inevitable particle growth and the destruction of delicate nanostructural features. Thus, the preparation of crystalline titania with tunable phase/particle size/morphology at low to moderate temperatures using a solution-based approach has paved the way for further exciting areas of research. In this focused review, titania synthesis from hydrothermal/solvothermal method, conventional sol-gel method and sol-gel-assisted method via ultrasonication, photoillumination and ILs, thermolysis and microemulsion routes are discussed. These wet chemical methods have broader visibility, since multiple reaction parameters, such as precursor chemistry, surfactants, chelating agents, solvents, mineralizer, pH of the solution, aging time, reaction temperature/time, inorganic electrolytes, can be easily manipulated to tune the final physical structure. This review sheds light on the stabilization/phase transformation pathways of titania polymorphs like anatase, rutile, brookite and TiO2(B) under a variety of reaction conditions. The driving force for crystallization arising from complex species in solution coupled with pH of the solution and ion species facilitating the orientation of octahedral resulting in a crystalline phase are reviewed in detail. In addition to titanium halide/alkoxide, the nucleation of titania from other precursors like peroxo and layered titanates are also discussed. The nonaqueous route and ball milling-induced titania transformation is briefly outlined; moreover, the lacunae in understanding the concepts and future prospects in this exciting field are suggested.

Conservation Properties of the Trapezoidal Rule in Linear Time Domain Analysis of Acoustics and Structures

The trapezoidal rule, which is a special case of the Newmark family of algorithms, is one of the most widely used methods for transient hyperbolic problems. In this work, we show that this rule conserves linear and angular momenta and energy in the case of undamped linear elastodynamics problems, and an ``energy-like measure'' in the case of undamped acoustic problems. These conservation properties, thus, provide a rational basis for using this algorithm. In linear elastodynamics problems, variants of the trapezoidal rule that incorporate ``high-frequency'' dissipation are often used, since the higher frequencies, which are not approximated properly by the standard displacement-based approach, often result in unphysical behavior. Instead of modifying the trapezoidal algorithm, we propose using a hybrid finite element framework for constructing the stiffness matrix. Hybrid finite elements, which are based on a two-field variational formulation involving displacement and stresses, are known to approximate the eigenvalues much more accurately than the standard displacement-based approach, thereby either bypassing or reducing the need for high-frequency dissipation. We show this by means of several examples, where we compare the numerical solutions obtained using the displacement-based and hybrid approaches against analytical solutions.

Structures of substrate- and nucleotide-bound propionate kinase from Salmonella typhimurium: substrate specificity and phosphate-transfer mechanism

Kinases are ubiquitous enzymes that are pivotal to many biochemical processes. There are contrasting views on the phosphoryl-transfer mechanism in propionate kinase, an enzyme that reversibly transfers a phosphoryl group from propionyl phosphate to ADP in the final step of non-oxidative catabolism of L-threonine to propionate. Here, X-ray crystal structures of propionate- and nucleotide-bound Salmonella typhimurium propionate kinase are reported at 1.8-2.0 angstrom resolution. Although the mode of nucleotide binding is comparable to those of other members of the ASKHA superfamily, propionate is bound at a distinct site deeper in the hydrophobic pocket defining the active site. The propionate carboxyl is at a distance of approximate to 5 angstrom from the -phosphate of the nucleotide, supporting a direct in-line transfer mechanism. The phosphoryl-transfer reaction is likely to occur via an associative S(N)2-like transition state that involves a pentagonal bipyramidal structure with the axial positions occupied by the nucleophile of the substrate and the O atom between the - and the -phosphates, respectively. The proximity of the strictly conserved His175 and Arg236 to the carboxyl group of the propionate and the -phosphate of ATP suggests their involvement in catalysis. Moreover, ligand binding does not induce global domain movement as reported in some other members of the ASKHA superfamily. Instead, residues Arg86, Asp143 and Pro116-Leu117-His118 that define the active-site pocket move towards the substrate and expel water molecules from the active site. The role of Ala88, previously proposed to be the residue determining substrate specificity, was examined by determining the crystal structures of the propionate-bound Ala88 mutants A88V and A88G. Kinetic analysis and structural data are consistent with a significant role of Ala88 in substrate-specificity determination. The active-site pocket-defining residues Arg86, Asp143 and the Pro116-Leu117-His118 segment are also likely to contribute to substrate specificity.

Structural characterization of a mitochondrial 3-ketoacyl-CoA (T1)-like thiolase from Mycobacterium smegmatis

Thiolases catalyze the degradation and synthesis of 3-ketoacyl-CoA molecules. Here, the crystal structures of a T1-like thiolase (MSM-13 thiolase) from Mycobacterium smegmatis in apo and liganded forms are described. Systematic comparisons of six crystallographically independent unliganded MSM-13 thiolase tetramers (dimers of tight dimers) from three different crystal forms revealed that the two tight dimers are connected to a rigid tetramerization domain via flexible hinge regions, generating an asymmetric tetramer. In the liganded structure, CoA is bound to those subunits that are rotated towards the tip of the tetramerization loop of the opposing dimer, suggesting that this loop is important for substrate binding. The hinge regions responsible for this rotation occur near Val123 and Arg149. The L alpha 1-covering loop-L alpha 2 region, together with the N beta 2-N alpha 2 loop of the adjacent subunit, defines a specificity pocket that is larger and more polar than those of other tetrameric thiolases, suggesting that MSM-13 thiolase has a distinct substrate specificity. Consistent with this finding, only residual activity was detected with acetoacetyl-CoA as the substrate in the degradative direction. No activity was observed with acetyl-CoA in the synthetic direction. Structural comparisons with other well characterized thiolases suggest that MSM-13 thiolase is probably a degradative thiolase that is specific for 3-ketoacyl-CoA molecules with polar, bulky acyl chains.

Damage assessment of composite plate structures with material and measurement uncertainty

Composite materials are very useful in structural engineering particularly in weight sensitive applications. Two different test models of the same structure made from composite materials can display very different dynamic behavior due to large uncertainties associated with composite material properties. Also, composite structures can suffer from pre-existing imperfections like delaminations, voids or cracks during fabrication. In this paper, we show that modeling and material uncertainties in composite structures can cause considerable problein in damage assessment. A recently developed C-0 shear deformable locking free refined composite plate element is employed in the numerical simulations to alleviate modeling uncertainty. A qualitative estimate of the impact of modeling uncertainty on the damage detection problem is made. A robust Fuzzy Logic System (FLS) with sliding window defuzzifier is used for delamination damage detection in composite plate type structures. The FLS is designed using variations in modal frequencies due to randomness in material properties. Probabilistic analysis is performed using Monte Carlo Simulation (MCS) on a composite plate finite element model. It is demonstrated that the FLS shows excellent robustness in delamination detection at very high levels of randomness in input data. (C) 2016 Elsevier Ltd. All rights reserved.

Large Scale Fabrication Of Periodical Bowl-Like Micropatterns Of Single Crystal Zno

Nanostructured ZnO materials are of great significance for their potential applications in photoelectronic devices, light-emitting displays, catalysis and gas sensors. In this paper, we report a new method to produce large area periodical bowl-like micropatterns of single crystal ZnO through aqueous-phase epitaxial growth on a ZnO single crystal substrate. A self-assembled monolayer of polystyrene microspheres was used as a template to confine the epitaxial growth of single crystal ZnO from the substrate, while the growth morphology was well controlled by citrate anions. Moreover, it was found that the self-assembled monolayer of colloidal spheres plays an important role in reduction of the defect density in the epitaxial ZnO layer. Though the mechanism is still open for further investigation, the present result indicates a new route to suppress the dislocations in the fabrication of single crystal ZnO film. A predicable application of this new method is for the fabrication of two-dimensional photonic crystal structures on light emitting diode surfaces.

A constitutive model for cavitation and cavity growth in rubber-like materials under arbitrary tri-axial loading

In this paper, we attempted to construct a constitutive model to deal with the phenomenon of cavitation and cavity growth in a rubber-like material subjected to an arbitrary tri-axial loading. To this end, we considered a spherical elementary representative volume in a general Rivlin's incompressible material containing a central spherical cavity. The kinematics proposed by [Hou, H.S., Abeyaratne, R., 1992. Cavitation in elastic and elastic-plastic solids. J. Mech. Phys. Solids 40, 571-722] was adopted in order to construct an approximate but optimal field. In order to establish a suitable constitutive law for this class of materials, we utilized the homogenisation technique that permits us to calculate the average strain energy density of the volume. The cavity growth was considered through a physically realistic failure criterion. Combination of the constitutive law and the failure criterion enables us to describe correctly the global behaviour and the damage evolution of the material under tri-axial loading. It was shown that the present models can efficiently reproduce different stress states, varying from uniaxial to tri-axial tensions, observed in experimentations. Comparison between predicted results and experimental data proves that the proposed model is accurate and physically reasonable. Another advantage is that the proposed model does not need special identification work, the initial Rivlin's law for the corresponding incompressible material is sufficient to form the new law for the compressible material resulted from cavitation procedure. (C) 2007 Elsevier Ltd. All rights reserved.

Cu2O substrates and epitaxial Cu2O/ZnO thin film hetero-structures for solar energy conversion

Future fossil fuel scarcity and environmental degradation have demonstrated the need for renewable, low-carbon sources of energy to power an increasingly industrialized world. Solar energy with its infinite supply makes it an extraordinary resource that should not go unused. However with current materials, adoption is limited by cost and so a paradigm shift must occur to get everyone on the same page embracing solar technology. Cuprous Oxide (Cu2O) is a promising earth abundant material that can be a great alternative to traditional thin-film photovoltaic materials like CIGS, CdTe, etc. We have prepared Cu2O bulk substrates by the thermal oxidation of copper foils as well Cu2O thin films deposited via plasma-assisted Molecular Beam Epitaxy. From preliminary Hall measurements it was determined that Cu2O would need to be doped extrinsically. This was further confirmed by simulations of ZnO/Cu2O heterojunctions. A cyclic interdependence between, defect concentration, minority carrier lifetime, film thickness, and carrier concentration manifests itself a primary reason for why efficiencies greater than 4% has yet to be realized. Our growth methodology for our thin-film heterostructures allow precise control of the number of defects that incorporate into our film during both equilibrium and nonequilibrium growth. We also report process flow/device design/fabrication techniques in order to create a device. A typical device without any optimizations exhibited open-circuit voltages Voc, values in excess 500mV; nearly 18% greater than previous solid state devices.

Travel time tomographic studies of seismic structures around subducted lithospheric slabs

The nature of the subducted lithospheric slab is investigated seismologically by tomographic inversions of ISC residual travel times. The slab, in which nearly all deep earthquakes occur, is fast in the seismic images because it is much cooler than the ambient mantle. High resolution three-dimensional P and S wave models in the NW Pacific are obtained using regional data, while inversion for the SW Pacific slabs includes teleseismic arrivals. Resolution and noise estimations show the models are generally well-resolved.

The slab anomalies in these models, as inferred from the seismicity, are generally coherent in the upper mantle and become contorted and decrease in amplitude with depth. Fast slabs are surrounded by slow regions shallower than 350 km depth. Slab fingering, including segmentation and spreading, is indicated near the bottom of the upper mantle. The fast anomalies associated with the Japan, Izu-Bonin, Mariana and Kermadec subduction zones tend to flatten to sub-horizontal at depth, while downward spreading may occur under parts of the Mariana and Kuril arcs. The Tonga slab appears to end around 550 km depth, but is underlain by a fast band at 750-1000 km depths.

The NW Pacific model combined with the Clayton-Comer mantle model predicts many observed residual sphere patterns. The predictions indicate that the near-source anomalies affect the residual spheres less than the teleseismic contributions. The teleseismic contributions may be removed either by using a mantle model, or using teleseismic station averages of residuals from only regional events. The slab-like fast bands in the corrected residual spheres are are consistent with seismicity trends under the Mariana Tzu-Bonin and Japan trenches, but are inconsistent for the Kuril events.

The comparison of the tomographic models with earthquake focal mechanisms shows that deep compression axes and fast velocity slab anomalies are in consistent alignment, even when the slab is contorted or flattened. Abnormal stress patterns are seen at major junctions of the arcs. The depth boundary between tension and compression in the central parts of these arcs appears to depend on the dip and topology of the slab.

Computational Predictions of G Protein-Coupled Receptor Structures and Binding Sites

G protein-coupled receptors (GPCRs) are the largest family of proteins within the human genome. They consist of seven transmembrane (TM) helices, with a N-terminal region of varying length and structure on the extracellular side, and a C-terminus on the intracellular side. GPCRs are involved in transmitting extracellular signals to cells, and as such are crucial drug targets. Designing pharmaceuticals to target GPCRs is greatly aided by full-atom structural information of the proteins. In particular, the TM region of GPCRs is where small molecule ligands (much more bioavailable than peptide ligands) typically bind to the receptors. In recent years nearly thirty distinct GPCR TM regions have been crystallized. However, there are more than 1,000 GPCRs, leaving the vast majority of GPCRs with limited structural information. Additionally, GPCRs are known to exist in a myriad of conformational states in the body, rendering the static x-ray crystal structures an incomplete reflection of GPCR structures. In order to obtain an ensemble of GPCR structures, we have developed the GEnSeMBLE procedure to rapidly sample a large number of variations of GPCR helix rotations and tilts. The lowest energy GEnSeMBLE structures are then docked to small molecule ligands and optimized. The GPCR family consists of five subfamilies with little to no sequence homology between them: class A, B1, B2, C, and Frizzled/Taste2. Almost all of the GPCR crystal structures have been of class A GPCRs, and much is known about their conserved interactions and binding sites. In this work we particularly focus on class B1 GPCRs, and aim to understand that family’s interactions and binding sites both to small molecules and their native peptide ligands. Specifically, we predict the full atom structure and peptide binding site of the glucagon-like peptide receptor and the TM region and small molecule binding sites for eight other class B1 GPCRs: CALRL, CRFR1, GIPR, GLR, PACR, PTH1R, VIPR1, and VIPR2. Our class B1 work reveals multiple conserved interactions across the B1 subfamily as well as a consistent small molecule binding site centrally located in the TM bundle. Both the interactions and the binding sites are distinct from those seen in the more well-characterized class A GPCRs, and as such our work provides a strong starting point for drug design targeting class B1 proteins. We also predict the full structure of CXCR4 bound to a small molecule, a class A GPCR that was not closely related to any of the class A GPCRs at the time of the work.

Fish pass design - criteria for the design and approval of fish passes and other structures to facilitate the passage of migratory fish in rivers

Many of British rivers hold stocks of salmon (Salmo salar L.) and sea trout (Salmo trutta L.) and during most of the year some of the adult fish migrate upstream to the head waters where, with the advent of winter, they will eventually spawn. For a variety of reasons, including the generation of power for milling, improving navigation and measuring water flow, man has put obstacles in the way of migratory fish which have added to those already provided by nature in the shape of rapids and waterfalls. While both salmon and sea trout, particularly the former, are capable of spectacular leaps the movement of fish over man-made and natural obstacles can be helped, or even made possible, by the judicious use of fish passes. These are designed to give the fish an easier route over or round an obstacle by allowing it to overcome the water head difference in a series of stages ('pool and traverse' fish pass) or by reducing the water velocity in a sloping channel (Denil fish pass). Salmon and sea trout make their spawning runs at different flow conditions, salmon preferring much higher water flows than sea trout. Hence the design of fish passes requires an understanding of the swimming ability of fish (speed and endurance) and the effect of water temperature on this ability. Also the unique features of each site must be appreciated to enable the pass to be positioned so that its entrance is readily located. As well as salmon and sea trout, rivers often have stocks of coarse fish and eels. Coarse fish migrations are generally local in character and although some obstructions such as weirs may allow downstream passages only, they do not cause a significant problem. Eels, like salmon and sea trout, travel both up and down river during the course of their life histories. However, the climbing power of elvers is legendary and it is not normally necessary to offer them help, while adult silver eels migrate at times of high water flow when downstream movement is comparatively easy: for these reasons neither coarse fish nor eels are considered further. The provision of fish passes is, in many instances, mandatory under the Salmon and Freshwater Fisheries Act 1975. This report is intended for those involved in the planning, siting, construction and operation of fish passes and is written to clarify the hydraulic problems for the biologist and the biological problems for the engineer. It is also intended to explain the criteria by which the design of an individual pass is assessed for Ministerial Approval.