<Emphasis Type="Italic">GlycomeDB</Emphasis> – integration of open-access carbohydrate structure databases

Background  

Although carbohydrates are the third major class of biological macromolecules, after proteins and DNA, there is neither a comprehensive database for carbohydrate structures nor an established universal structure encoding scheme for computational purposes. Funding for further development of the Complex Carbohydrate Structure Database (CCSD or CarbBank) ceased in 1997, and since then several initiatives have developed independent databases with partially overlapping foci. For each database, different encoding schemes for residues and sequence topology were designed. Therefore, it is virtually impossible to obtain an overview of all deposited structures or to compare the contents of the various databases.     

BRAGI: linking and visualization of database information in a 3D viewer and modeling tool

BRAGI is a well-established package for viewing and modeling of three-dimensional (3D) structures of biological macromolecules. A new version of BRAGI has been developed that is supported on Windows, Linux and SGI. The user interface has been rewritten to give the standard 'look and feel' of the chosen operating system and to provide a more intuitive, easier usage. A large number of new features have been added. Information from public databases such as SWISS-PROT, InterPro, DALI and OMIM can be displayed in the 3D viewer. Structures can be searched for homologous sequences using the NCBI BLAST server.     

Facilities that make the PDB data collection more powerful

We describe a series of databases and tools that directly or indirectly support biomedical research on macromolecules, with focus on their applicability in protein structure bioinformatics research. DSSP, that determines secondary structures of proteins, has been updated to work well with extremely large structures in multiple formats. The PDBREPORT database that lists anomalies in protein structures has been remade to remove many small problems. These reports are now available as PDF‐formatted files with a computer‐readable summary. The VASE software has been added to analyze and visualize HSSP multiple sequence alignments for protein structures. The Lists collection of databases has been extended with a series of databases, most noticeably with a database that gives each protein structure a grade for usefulness in protein structure bioinformatics projects. The PDB‐REDO collection of reanalyzed and re‐refined protein structures that were solved by X‐ray crystallography has been improved by dealing better with sugar residues and with hydrogen bonds, and adding many missing surface loops. All academic software underlying these protein structure bioinformatics applications and databases are now publicly accessible, either directly from the authors or from the GitHub software repository.     

基于设计的生物大分子成药性优化策略研究进展

目前生物药物正处在高速发展阶段,但生物大分子的一些固有特性限制了其成药性,使得很多具有良好治疗潜能的生物大分子 最终不能开发成药物,因而严重制约了生物药物的发展。生物药物开发的瓶颈已从“新分子的产生”转向“如何获得具有优良生理特性 和预期治疗效果的有效药物”。近年来,通过合理设计改造生物大分子高级结构以优化其成药性的研究获得了快速发展。综述基于设计 的生物大分子成药性优化策略研究进展。     

A framework for querying a database for structural information on 3D images of macromolecules: A web-based query-by-content prototype on the BioImage macromolecular server

Nowadays we are experiencing a remarkable growth in the number of databases that have become accessible over the Web. However, in a certain number of cases, for example, in the case of BioImage, this information is not of a textual nature, thus posing new challenges in the design of tools to handle these data. In this work, we concentrate on the development of new mechanisms aimed at "querying" these databases of complex data sets by their intrinsic content, rather than by their textual annotations only. We concentrate our efforts on a subset of BioImage containing 3D images (volumes) of biological macromolecules, implementing a first prototype of a "query-by-content" system. In the context of databases of complex data types the term query-by-content makes reference to those data modeling techniques in which user-defined functions aim at "understanding" (to some extent) the informational content of the data sets. In these systems the matching criteria introduced by the user are related to intrinsic features concerning the 3D images themselves, hence, complementing traditional queries by textual key words only. Efficient computational algorithms are required in order to "extract" structural information of the 3D images prior to storing them in the database. Also, easy-to-use interfaces should be implemented in order to obtain feedback from the expert. Our query-by-content prototype is used to construct a concrete query, making use of basic structural features, which are then evaluated over a set of three-dimensional images of biological macromolecules. This experimental implementation can be accessed via the Web at the BioImage server in Madrid, at http://www.bioimage.org/qbc/index.html.     

The RNA structure alignment ontology

Multiple sequence alignments are powerful tools for understanding the structures, functions, and evolutionary histories of linear biological macromolecules (DNA, RNA, and proteins), and for finding homologs in sequence databases. We address several ontological issues related to RNA sequence alignments that are informed by structure. Multiple sequence alignments are usually shown as two-dimensional (2D) matrices, with rows representing individual sequences, and columns identifying nucleotides from different sequences that correspond structurally, functionally, and/or evolutionarily. However, the requirement that sequences and structures correspond nucleotide-by-nucleotide is unrealistic and hinders representation of important biological relationships. High-throughput sequencing efforts are also rapidly making 2D alignments unmanageable because of vertical and horizontal expansion as more sequences are added. Solving the shortcomings of traditional RNA sequence alignments requires explicit annotation of the meaning of each relationship within the alignment. We introduce the notion of “correspondence,” which is an equivalence relation between RNA elements in sets of sequences as the basis of an RNA alignment ontology. The purpose of this ontology is twofold: first, to enable the development of new representations of RNA data and of software tools that resolve the expansion problems with current RNA sequence alignments, and second, to facilitate the integration of sequence data with secondary and three-dimensional structural information, as well as other experimental information, to create simultaneously more accurate and more exploitable RNA alignments.     

Small-angle scattering: a view on the properties, structures and structural changes of biological macromolecules in solution

A self-contained presentation of the main concepts and methods for interpretation of X-ray and neutron-scattering patterns of biological macromolecules in solution, including a reminder of the basics of X-ray and neutron scattering and a brief overview of relevant aspects of modern instrumentation, is given. For monodisperse solutions the experimental data yield the scattering intensity of the macromolecules, which depends on the contrast between the solvent and the particles as well as on their shape and internal scattering density fluctuations, and the structure factor, which is related to the interactions between macromolecules. After a brief analysis of the information content of the scattering intensity, the two main approaches for modelling the shape and/or structure of macromolecules and the global minimization schemes used in the calculations are presented. The first approach is based, in its more advanced version, on the spherical harmonics approximation and relies on few parameters, whereas the second one uses bead models with thousands of parameters. Extensions of bead modelling can be used to model domain structure and missing parts in high-resolution structures. Methods for computing the scattering patterns from atomic models including the contribution of the hydration shell are discussed and examples are given, which also illustrate that significant differences sometimes exist between crystal and solution structures. These differences are in some cases explainable in terms of rigid-body motions of parts of the structures. Results of two extensive studies--on ribosomes and on the allosteric protein aspartate transcarbamoylase--illustrate the application of the various methods. The unique bridge between equilibrium structures and thermodynamic or kinetic aspects provided by scattering techniques is illustrated by modelling of intermolecular interactions, including crystallization, based on an analysis of the structure factor and recent time-resolved work on assembly and protein folding.     

1D2DSimScore: A novel method for comparing contacts in biomacromolecules and their complexes

The biologically relevant structures of proteins and nucleic acids and their complexes are dynamic. They include a combination of regions ranging from rigid structural segments to structural switches to regions that are almost always disordered, which interact with each other in various ways. Comparing conformational changes and variation in contacts between different conformational states is essential to understand the biological functions of proteins, nucleic acids, and their complexes. Here, we describe a new computational tool, 1D2DSimScore, for comparing contacts and contact interfaces in all kinds of macromolecules and macromolecular complexes, including proteins, nucleic acids, and other molecules. 1D2DSimScore can be used to compare structural features of macromolecular models between alternative structures obtained in a particular experiment or to score various predictions against a defined “ideal” reference structure. Comparisons at the level of contacts are particularly useful for flexible molecules, for which comparisons in 3D that require rigid-body superpositions are difficult, and in biological systems where the formation of specific inter-residue contacts is more relevant for the biological function than the maintenance of a specific global 3D structure. Similarity/dissimilarity scores calculated by 1D2DSimScore can be used to complement scores describing 3D structural similarity measures calculated by the existing tools.     

蛋白质相互作用数据库

随着“蛋白质组学”的蓬勃发展和人类对生物大分子功能机制的知识积累,涌现出海量的蛋白质相互作用数据。随之,研究者开发了300多个蛋白质相互作用数据库,用于存储、展示和数据的重利用。蛋白质相互作用数据库是系统生物学、分子生物学和临床药物研究的宝贵资源。本文将数据库分为3类：（1）综合蛋白质相互作用数据库;（2）特定物种的蛋白质相互作用数据库;（3）生物学通路数据库。重点介绍常用的蛋白质相互作用数据库,包括BioGRID、STRING、IntAct、MINT、DIP、IMEx、HPRD、Reactome和KEGG等。     

From sequence to 3D structure of hyperbranched molecules: application to surface modified PAMAM dendrimers

The molecular modeling of hyperbranched molecules is currently constrained by difficulties in model building, due partly to lack of parameterization of their building blocks. We have addressed this problem with specific relevance to a class of hyperbranched macromolecules known as dendrimers by describing a new concept and developing a method that translates monomeric linear sequences into a full atomistic model of a hyperbranched molecule. Such molecular-modeling-based advances will enable modeling studies of important biological interactions between naturally occurring macromolecules and synthetic macromolecules. Our results also suggest that it should be possible to apply this sequence-based methodology to generate hyperbranched structures of other dendrimeric structures and of linear polymers.     

SWISS-PROT: connecting biomolecular knowledge via a protein database

With the explosive growth of biological data, the development of new means of data storage was needed. More and more often biological information is no longer published in the conventional way via a publication in a scientific journal, but only deposited into a database. In the last two decades these databases have become essential tools for researchers in biological sciences. Biological databases can be classified according to the type of information they contain. There are basically three types of sequence-related databases (nucleic acid sequences, protein sequences and protein tertiary structures) as well as various specialized data collections. It is important to provide the users of biomolecular databases with a degree of integration between these databases as by nature all of these databases are connected in a scientific sense and each one of them is an important piece to biological complexity. In this review we will highlight our effort in connecting biological information as demonstrated in the SWISS-PROT protein database.     

Electronic excitations in condensed biological matter

In living matter, electronic excitations may have a collective character which is reviewed here in simple physical terms. In liquids and ordered solids the collective excitations appear as plasmons or excitons. Plasmons are delocalized electronic perturbations of a huge number of oscillating electrons decaying very quickly into localized electronic perturbations, mainly low-energy ionizations. Excitons are very light, moving quantum quasi-particles carrying energy, charge and information in structured biological systems. In deformable soft structures collective excitations appear as solitons behaving as rather massive quasi-particles of combined quantum and classical character. Solitons are relatively stable micro-objects able to transfer energy, charge, mass, and biological information along such biological structures as (chains of) macromolecules, fibres, membranes and surfaces. Some photobiological and radiation biological consequences of collective electronic excitations are suggested.     

Protein Structure Databases

Web-based protein structure databases come in a wide variety of types and levels of information content. Those having the most general interest are the various atlases that describe each experimentally determined protein structure and provide useful links, analyses and schematic diagrams relating to its 3D structure and biological function. Also of great interest are the databases that classify 3D structures by their folds as these can reveal evolutionary relationships which may be hard to detect from sequence comparison alone. Related to these are the numerous servers that compare folds—particularly useful for newly solved structures, and especially those of unknown function. Beyond these there are a vast number of databases for the most specialized user, dealing with specific families, diseases, structural features and so on.     

Normal mode analysis with simplified models to investigate the global dynamics of biological systems

Dynamical properties of macromolecules are increasingly being recognized as significantly contributing to biological functions, including catalysis, regulation of activity, etc. In this review, theoretical approaches to the study of dynamics of biological systems and their application are discussed. In particular, simplified models for the normal mode analysis are described.     

Using surface envelopes for discrimination of molecular models

Shape information about macromolecules is increasingly available but is difficult to use in modeling efforts. We demonstrate that shape information alone can often distinguish structural models of biological macromolecules. By using a data structure called a surface envelope (SE) to represent the shape of the molecule, we propose a method that generates a fitness score for the shape of a particular molecular model. This score correlates well with root mean squared deviation (RMSD) of the model to the known test structures and can be used to filter models in decoy sets. The scoring method requires both alignment of the model to the SE in three-dimensional space and assessment of the degree to which atoms in the model fill the SE. Alignment combines a hybrid algorithm using principal components and a previously published iterated closest point algorithm. We test our method against models generated from random atom perturbation from crystal structures, published decoy sets used in structure prediction, and models created from the trajectories of atoms in molecular modeling runs. We also test our alignment algorithm against experimental electron microscopic data from rice dwarf virus. The alignment performance is reliable, and we show a high correlation between model RMSD and score function. This correlation is stronger for molecular models with greater oblong character (as measured by the ratio of largest to smallest principal component).     

BioMOBY successfully integrates distributed heterogeneous bioinformatics Web Services. The PlaNet exemplar case

The burden of non-interoperability between on-line genomic resources is increasingly the rate-limiting step in large-scale genomic analysis. BioMOBY is a biological Web Service interoperability initiative that began as a retreat of representatives from the model organism database community in September, 2001. Its long-term goal is to provide a simple, extensible platform through which the myriad of on-line biological databases and analytical tools can offer their information and analytical services in a fully automated and interoperable way. Of the two branches of the larger BioMOBY project, the Web Services branch (MOBY-S) has now been deployed over several dozen data sources worldwide, revealing some significant observations about the nature of the integrative biology problem; in particular, that Web Service interoperability in the domain of bioinformatics is, unexpectedly, largely a syntactic rather than a semantic problem. That is to say, interoperability between bioinformatics Web Services can be largely achieved simply by specifying the data structures being passed between the services (syntax) even without rich specification of what those data structures mean (semantics). Thus, one barrier of the integrative problem has been overcome with a surprisingly simple solution. Here, we present a non-technical overview of the critical components that give rise to the interoperable behaviors seen in MOBY-S and discuss an exemplar case, the PlaNet consortium, where MOBY-S has been deployed to integrate the on-line plant genome databases and analytical services provided by a European consortium of databases and data service providers.     

Bioactive peptide design using the Resonant Recognition Model

With a large number of DNA and protein sequences already known, the crucial question is to find out how the biological function of these macromolecules is "written" in the sequence of nucleotides or amino acids. Biological processes in any living organism are based on selective interactions between particular bio-molecules, mostly proteins. The rules governing the coding of a protein's biological function, i.e. its ability to selectively interact with other molecules, are still not elucidated. In addition, with the rapid accumulation of databases of protein primary structures, there is an urgent need for theoretical approaches that are capable of analysing protein structure-function relationships. The Resonant Recognition Model (RRM) [1, 2] is one attempt to identify the selectivity of protein interactions within the amino acid sequence. The RRM [1, 2] is a physico-mathematical approach that interprets protein sequence linear information using digital signal processing methods. In the RRM the protein primary structure is represented as a numerical series by assigning to each amino acid in the sequence a physical parameter value relevant to the protein's biological activity. The RRM concept is based on the finding that there is a significant correlation between spectra of the numerical presentation of amino acids and their biological activity. Once the characteristic frequency for a particular protein function/interaction is identified, it is possible then to utilize the RRM approach to predict the amino acids in the protein sequence, which predominantly contribute to this frequency and thus, to the observed function, as well as to design de novo peptides having the desired periodicities. As was shown in our previous studies of fibroblast growth factor (FGF) peptidic antagonists [2, 3] and human immunodeficiency virus (HIV) envelope agonists [2, 4], such de novo designed peptides express desired biological function. This study utilises the RRM computational approach to the analysis of oncogene and proto-oncogene proteins. The results obtained have shown that the RRM is capable of identifying the differences between the oncogenic and proto-oncogenic proteins with the possibility of identifying the "cancer-causing" features within their protein primary structure. In addition, the rational design of bioactive peptide analogues displaying oncogenic or proto-oncogenic-like activity is presented here.     

Polarization optical analysis of blood cell membranes

The present study deals with investigations of membrane structure using polarization topo-optical reactions. Polarization microscopy is a special field of biological submicroscopic morphology. It represents a powerful tool well able to reveal the features of organization of biological structures, and the regularity of macromolecules building cells and tissues - properties that cannot directly be studied by other approaches to complex biological systems. Only in "pure" systems can X-ray diffraction, or the analysis of circular dichroism and the dispersion of optical rotability provide data equivalent to those obtained by polarization microscopy in complex systems. One of the main drawbacks of molecular biology is that most information is relevant to isolated, purified particles or macromolecules. Thus, no conclusions can be drawn concerning the original arrangement of molecules. The gap between biochemical-biophysical and morphological approaches to molecular arrangement in complex structures is bridged by the polarization optical technique. As was pointed out in the introduction, polarization microscopy became a routine biological research method following the pioneering work of Romhányi. His enlightening topo-optical reactions (Romhányi 1960, 1963, 1966) were based on the oriented dye binding of the original charge carriers of regularly arranged tissue constituents. The second group of Romhányi's topo-optical reactions comprised procedures such as sulfation (Romhányi et al. 1973, 1974), the aldehyde-bisulfite-toluidine blue (ABT) reaction (Romhányi et al. 1974, 1975), the permanganate-bisulfite-toluidine blue (PBT) reaction (Fischer 1979, 1979a), and the sialic acid-specific reaction (Makovitzky 1980) all of which operate with induced dye-binding groups; i.e. dye-binding moieties on biological macromolecules are produced by specific chemical reactions.     

Timeline: the march of structural biology

One hundred years ago, we knew very little about biological macromolecules and had no tools available to study their structure. Structural biology is now a mature science. New structures are being solved at an ever-increasing rate and there are important new initiatives to determine all the protein folds that are used by biological systems (structural genomics). This article traces some of the key developments in the field.     

Spectroscopic studies of methylglyoxal in water and dimethylsulfoxide

Methylglyoxal is a highly reactive dicarbonyl compound, which reacts in vivo with biological macromolecules and thereby affects their structure and function. These changes are associated with complications during aging, diabetes and Alzheimer's disease as well as with growth inhibition in different tumors. Many enzymes are involved in the metabolism of methylglyoxal, but its true physiological role in metabolism and chemical properties are still obscure. In this study it was shown that methylglyoxal, during the freeze-drying of aqueous solutions, polymerizes into small polymeric structures which are stable in organic media such as dimethylsulfoxide. When re-exposed to water, the polymers are immediately transformed into the monomeric mono- and dihydrate forms of methylglyoxal. By NMR and UV spectroscopy, it was shown that solvent, temperature, and the amount of available water strongly influence the equilibrium of the different forms of methylglyoxal and thereby change its reactivity. 1H and 13C NMR spectroscopy were used to determine the structures of the different monomeric and oligomeric structures of methylglyoxal.