Identification of protein biochemical functions by similarity search using the molecular surface database eF-site

The identification of protein biochemical functions based on their three-dimensional structures is strongly required in the post-genome-sequencing era. We have developed a new method to identify and predict protein biochemical functions using the similarity information of molecular surface geometries and electrostatic potentials on the surfaces. Our prediction system consists of a similarity search method based on a clique search algorithm and the molecular surface database eF-site (electrostatic surface of functional-site in proteins). Using this system, functional sites similar to those of phosphoenoylpyruvate carboxy kinase were detected in several mononucleotide-binding proteins, which have different folds. We also applied our method to a hypothetical protein, MJ0226 from Methanococcus jannaschii, and detected the mononucleotide binding site from the similarity to other proteins having different folds.     

Protein-protein networks construction and their relevance measurement based on multi-epitope-ligand-kartographie and gene ontology data of T-cell surface proteins for polymyositis

Polymyositis is an inflammatory myopathy characterized by muscle invasion of T-cells penetrating the basal lamina and displacing the plasma membrane of normal muscle fibers. In order to understand the different adhesive mechanisms at the T-cell surface, Schubert randomly selected 19 proteins expressed at the T-cell surface and studied them using MELK technique [4], among which 15 proteins are picked up for further study by us. Two types of functional similarity networks are constructed for these proteins. The first type is MELK similarity network, which is constructed based on their MELK data by using the McNemar's test [24]. The second type is GO similarity network, which is constructed based on their GO annotation data by using the RSS method to measuring functional similarity. Then the subset surprisology theory is employed to measure the degree of similarity between two networks. Our computing results show that these two types of networks are high related. This conclusion added new values on MELK technique and expanded its applications greatly.     

Protein Functional Surfaces: Global Shape Matching and Local Spatial Alignments of Ligand Binding Sites

Background

Protein surfaces comprise only a fraction of the total residues but are the most conserved functional features of proteins. Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity. While biochemical activity can be attributed to a few key residues, the broader surrounding environment plays an equally important role.

Results

We describe a methodology that attempts to optimize two components, global shape and local physicochemical texture, for evaluating the similarity between a pair of surfaces. Surface shape similarity is assessed using a three-dimensional object recognition algorithm and physicochemical texture similarity is assessed through a spatial alignment of conserved residues between the surfaces. The comparisons are used in tandem to efficiently search the Global Protein Surface Survey (GPSS), a library of annotated surfaces derived from structures in the PDB, for studying evolutionary relationships and uncovering novel similarities between proteins.

Conclusion

We provide an assessment of our method using library retrieval experiments for identifying functionally homologous surfaces binding different ligands, functionally diverse surfaces binding the same ligand, and binding surfaces of ubiquitous and conformationally flexible ligands. Results using surface similarity to predict function for proteins of unknown function are reported. Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.     

中国云南部分小兽体表吸虱昆虫群落相似性及群落分类研究(英文)

应用系统聚类分析方法对云南省境内24种主要小型哺乳动物(小兽)体表吸虱昆虫群落相似性及群落分类进行了研究。研究中将每一种小兽体表的所有吸虱昆虫定义为一个相应的吸虱群落单位。结果表明,小兽体表吸虱群落结构简单,物种多样性很低。多数小兽有固定的吸虱种类寄生,其吸虱的宿主特异性高。在动物分类上隶属同一个属的小兽,其体表吸虱群落相似程度高,在系统聚类分析中大多被归为一类。在动物分类上近缘的小兽,其体表吸虱群落相似,优势虱种相同或相似,此情形尤其表现在鼠属、白腹鼠属、姬鼠属和绒鼠属。吸虱群落相似性大小与相应小兽宿主在动物分类地位上的近缘性高低呈现高度一致。从生态学角度来看,吸虱昆虫与其所寄生的小兽宿主动物之间存在密切的协同进化关系。     

Mixed Convection Boundary Layer Flow over a Moving Vertical Flat Plate in an External Fluid Flow with Viscous Dissipation Effect

The steady boundary layer flow of a viscous and incompressible fluid over a moving vertical flat plate in an external moving fluid with viscous dissipation is theoretically investigated. Using appropriate similarity variables, the governing system of partial differential equations is transformed into a system of ordinary (similarity) differential equations, which is then solved numerically using a Maple software. Results for the skin friction or shear stress coefficient, local Nusselt number, velocity and temperature profiles are presented for different values of the governing parameters. It is found that the set of the similarity equations has unique solutions, dual solutions or no solutions, depending on the values of the mixed convection parameter, the velocity ratio parameter and the Eckert number. The Eckert number significantly affects the surface shear stress as well as the heat transfer rate at the surface.     

Inferring functional relationships of proteins from local sequence and spatial surface patterns

We describe a novel approach for inferring functional relationship of proteins by detecting sequence and spatial patterns of protein surfaces. Well-formed concave surface regions in the form of pockets and voids are examined to identify similarity relationship that might be directly related to protein function. We first exhaustively identify and measure analytically all 910,379 surface pockets and interior voids on 12,177 protein structures from the Protein Data Bank. The similarity of patterns of residues forming pockets and voids are then assessed in sequence, in spatial arrangement, and in orientational arrangement. Statistical significance in the form of E and p-values is then estimated for each of the three types of similarity measurements. Our method is fully automated without human intervention and can be used without input of query patterns. It does not assume any prior knowledge of functional residues of a protein, and can detect similarity based on surface patterns small and large. It also tolerates, to some extent, conformational flexibility of functional sites. We show with examples that this method can detect functional relationship with specificity for members of the same protein family and superfamily, as well as remotely related functional surfaces from proteins of different fold structures. We envision that this method can be used for discovering novel functional relationship of protein surfaces, for functional annotation of protein structures with unknown biological roles, and for further inquiries on evolutionary origins of structural elements important for protein function.     

SIMILARITY COMPARISON AND CLASSIFICATION OF SUCKING LOUSE COMMUNITIES ON SOME SMALL MAMMALS IN YUNNAN, CHINA

Abstract  The similarity and classification of sucking louse communities on 24 species of small mammals were studied in Yunnan Province, China, through a hierarchical cluster analysis. All the louse species on the body surface of a certain species of small mammals are regarded as a louse community unit. The results reveal that the community structure of sucking lice on small mammals is simple with low species diversity. Most small mammals usually have certain louse species on their body surface; there exists a high degree of host specificity. Most louse communities on the same genus of small mammals show a high similarity and are classified into the same group based on hierarchical cluster analysis. When the hosts have a close affinity in taxonomy, the louse communities on their body surface would tend to be similar with the same or similar dominant louse species (as observed in genus Rattus, Niviventer, Apodemus and Eothenomys ). The similarity of sucking louse communities is highly consistent with the affinity of small mammal hosts in taxonomy. The results suggest a close relationship of co-evolution between sucking lice and their hosts.     

Self similarity of protein surfaces.

Scaling properties of the surfaces of 53 proteins are studied on the basis of experimentally determined 3-D structures of these biological macromolecules. It is found that the surfaces show self similarity within a yardstick range of 1.5 A less than epsilon less than 15 A. The self similarity is measured by the fractal dimension D of the surface. Two different algorithms for the determination of the fractal dimension are applied, both based on cubic yardstick particles. One is related to the contact surface (CS), which was first introduced by Connolly (17), while the other corresponds to the solvent accessible surface (SAS) of Richards (9). The fractal dimensions of both are different. While the CS type approach leads to relatively high values of D in the range 2.5 to 2.6 the SAS approach gives fractal dimensions of D approximately 2.     

现生微生物群落形态研究及其对解释埃迪卡拉生物群化石属性的启示

通过对常见微生物种类进行纯培养获得多种微生物菌落形态,并将其与埃迪卡拉生物群化石形态进行对比研究,发现：1）盘状化石Aspidella与圆盘形菌落的轮廓和放射状分布的小脊具有相似性;2）“rangeomorphs”分支状化石与具有次级分支结构的菌落具有某些相似性;3）五边形似棘皮动物化石Arkaruaadami与五边形菌落较为相似;4）两侧对称类化石Kimberella与圆盘形边缘具放射状脊的菌落的表面形态非常相似;5）盘状化石Az—bumaresbrunsae与圆盘形表面具辐射状脊的菌落的轮廓和表面纹饰分布极为相似。以上对比结果表明部分埃迪卡拉生物群化石与微生物菌落形态具有一定的相似性。本研究为埃迪卡拉生物群化石生物属性的解译提供了新思路。     

ParaFrag—an approach for surface-based similarity comparison of molecular fragments

A frequent task in computer-aided drug design is to identify novel chemotypes similar in activity but structurally different to a given reference structure. Here we report the development of a novel method for atom-independent similarity comparison of molecular fragments (substructures of drug-like molecules). The fragments are characterized by their local surface properties coded in the form of 3D pharmacophores. As surface properties, we used the electrostatic potential (MEP), the local ionization energy (IE_L), local electron affinity (EA_L) and local polarizability (POL) calculated on isodensity surfaces. A molecular fragment can then be represented by a minimal set of extremes for each surface property. We defined a tolerance sphere for each of these extremes, thus allowing us to assess the similarity of fragments in an analogous manner to classical pharmacophore comparison. As a first application of this method we focused on comparing rigid fragments suitable for scaffold hopping. A retrospective analysis of successful scaffold hopping reported for Factor Xa inhibitors [Wood MR et al (2006) J Med Chem 49:1231] showed that our method performs well where atom-based similarity metrics fail. Figure Encoding surface hotspots as a ParaFrag pharmacophore     

Reliable Identification of Deep Sulcal Pits: The Effects of Scan Session,Scanner, and Surface Extraction Tool

Sulcal pit analysis has been providing novel insights into brain function and development. The purpose of this study was to evaluate the reliability of sulcal pit extraction with respect to the effects of scan session, scanner, and surface extraction tool. Five subjects were scanned 4 times at 3 MRI centers and other 5 subjects were scanned 3 times at 2 MRI centers, including 1 test-retest session. Sulcal pits were extracted on the white matter surfaces reconstructed with both Montreal Neurological Institute and Freesurfer pipelines. We estimated similarity of the presence of sulcal pits having a maximum value of 1 and their spatial difference within the same subject. The tests showed high similarity of the sulcal pit presence and low spatial difference. The similarity was more than 0.90 and the spatial difference was less than 1.7 mm in most cases according to different scan sessions or scanners, and more than 0.85 and about 2.0 mm across surface extraction tools. The reliability of sulcal pit extraction was more affected by the image processing-related factors than the scan session or scanner factors. Moreover, the similarity of sulcal pit distribution appeared to be largely influenced by the presence or absence of the sulcal pits on the shallow and small folds. We suggest that our sulcal pit extraction from MRI is highly reliable and could be useful for clinical applications as an imaging biomarker.     

The beauty of molecular surfaces as revealed by self-organizing neural networks

The Kohonen neural network is a self-organizing network that can be used for the projection of the surface properties of molecules. This allows one to view properties on a molecular surface, like the electrostatic potential in a single picture. These maps are useful for the comparison of molecules and provide a new definition of molecular similarity.     

Diversity patterns in terrestrial dipteran communities

1. Dipteran communities were studied in five terrestrial habitats [beech forest (BE), oak and hornbeam forest (OH), hedgerow (HE), meadow (ME), alder and willow forest (AW)] using emergence traps and diversity patterns of three trophic groups with soil-dwelling larvae (zoophages, phytosaprophages and surface scrapers) were analysed in detail.
2. Across habitats, sampling effort was a poor predictor of species richness, and species richness increased more steeply with sample size in the zoophages than in the phytosaprophages and surface scrapers.
3. Point diversity (S/trap) of phytosaprophages and surface scrapers increased (as predicted) with resource heterogeneity in the litter layer, but that of zoophages did not. It is suggested that this may be due to differential resource requirements of the three trophic groups during adult life.
4. Zoophages attained the highest and surface scrapers the lowest values of Shannon diversity, while phytosaprophages were intermediate.
5. Predator:prey ratios differed between habitats; they were particularly high in the meadow and low in the oak and hornbeam forest communities.
6. Species identity (Sorensen index) of soil-dwelling Diptera arranged habitats in an order of decreasing similarity (BE–OH–HE–ME–AW), but percentage similarity indicated a closer relationship between the meadow and the hedgerow communities [BE–OH–AW–(HE–ME)]. Functional similarity, which was based on the proportional biomass of differently sized trophic groups, was highest between the BE and OH communities, i.e. in the habitats most similar in litter layer and vegetation structure.     

Recognition of ERK MAP kinase by PEA-15 reveals a common docking site within the death domain and death effector domain

PEA-15 is a multifunctional protein that modulates signaling pathways which control cell proliferation and cell death. In particular, PEA-15 regulates the actions of the ERK MAP kinase cascade by binding to ERK and altering its subcellular localization. The three-dimensional structure of PEA-15 has been determined using NMR spectroscopy and its interaction with ERK defined by characterization of mutants that modulate ERK function. PEA-15 is composed of an N-terminal death effector domain (DED) and a C-terminal tail of irregular structure. NMR 'footprinting' and mutagenesis identified elements of both the DED and tail that are required for ERK binding. Comparison of the DED-binding surface for ERK2 with the death domain (DD)-binding surface of Drosophila Tube revealed an unexpected similarity between the interaction modes of the DD and DED motifs in these proteins. Despite a lack of functional or sequence similarity between PEA-15 and Tube, these proteins utilize a common surface of the structurally similar DD and DED to recognize functionally diverse targets.     

Morphological correlates of diet in an assemblage of West African freshwater fishes

Morphological correlates of diet were sought among 18 species of distantly related freshwater fishes from Guinea (West Africa). With regard to the percentage occurrence of six food items, the studied species could be classified into four broad trophic categories reflecting what was eaten and where: detritivores, piscivores, surface feeders and benthic invertivores. Detrivory was associated with a high relative gut length and eyes in a dorsal position; piscivory with large body and mouth size; surface feeding with a dorsally orientated mouth; and benthic invertivory with eyes in a lateral position and small relative gut length. Similarity in diet and in morphology were both significantly correlated with taxonomic relatedness. Nevertheless, when taxonomic relatedness was accounted for, the relationship between observed similarity in diet and similarity in diet predicted from morphology was still significant. This result leads to the conclusion that species having similar diet tend to converge for some morphological attributes.     

Cysteine residue periodicity is a conserved structural feature of variable surface proteins from Paramecium tetraurelia.

The DNA sequences of the entire coding regions of the A and C type variable surface protein genes from Paramecium tetraurelia, stock 51 have been determined. The 8151 nucleotide open reading frame of the A gene contains several tandem repeats of 210 nucleotides within the central portion of the molecule as well as a periodic structure defined by cysteine residues. The 6699 nucleotide open reading frame of the C gene does not contain any identifiable tandem repeats or internal similarity but maintains a periodicity based on the cysteine residue spacing. The deduced amino acid sequences encoded by the two genes are most similar within the 600 amino-terminal and 600 carboxyl-terminal amino acid residues, the central portions show only limited sequence similarity. We conclude that internal repeats are not a conserved feature of variable surface proteins in Paramecium and discuss the possible importance of the regular pattern of cysteine residues.     

Predicted effects of climate change on potential sources of non‐indigenous marine species

Aim

We compare the present‐day global ocean climate with future climatologies based on Intergovernmental Panel on Climate Change (IPCC) models and examine whether changes in global ocean climate will affect the environmental similarity of New Zealand's (NZ) coastal environments to those of the rest of the world. Our underlying rationale is that environmental changes to source and recipient regions may result in changes to the risk of non‐indigenous species survival and establishment.

Location

Coastlines of global continents and islands.

Methods

We determined the environmental similarity (Euclidean distance) between global coastlines and north‐east NZ for 2005 and 2050 using data on coastal seawater surface temperature and salinity. Anticipated climate models from the SRES A1B scenario family were used to derive coastal climatologies for 2050.

Results

During the next decades, most global regions will experience an increase in coastal seawater surface temperatures and a decline or increase in salinity. This will result in changes in the similarity of other coastal environments to north‐east NZ's coastal areas. Global regions that presently have high environmental similarity to north‐east NZ will variously retain this level of similarity, become more similar or decrease in environmental similarity. Some regions that presently have a low level of similarity will become more similar to NZ. Our models predict a widespread decrease in the seasonal variation in environmental similarity to NZ.

Main conclusions

Anticipated changes in the global ocean climate have the potential to change the risk of survival and establishment of non‐indigenous marine species arriving to NZ from some global regions. Predicted changes to global human transport networks over the coming decades highlight the importance of incorporating climate change into conservation planning and modelling.

     

Identification of Distant Drug Off-Targets by Direct Superposition of Binding Pocket Surfaces

Correctly predicting off-targets for a given molecular structure, which would have the ability to bind a large range of ligands, is both particularly difficult and important if they share no significant sequence or fold similarity with the respective molecular target (“distant off-targets”). A novel approach for identification of off-targets by direct superposition of protein binding pocket surfaces is presented and applied to a set of well-studied and highly relevant drug targets, including representative kinases and nuclear hormone receptors. The entire Protein Data Bank is searched for similar binding pockets and convincing distant off-target candidates were identified that share no significant sequence or fold similarity with the respective target structure. These putative target off-target pairs are further supported by the existence of compounds that bind strongly to both with high topological similarity, and in some cases, literature examples of individual compounds that bind to both. Also, our results clearly show that it is possible for binding pockets to exhibit a striking surface similarity, while the respective off-target shares neither significant sequence nor significant fold similarity with the respective molecular target (“distant off-target”).