The Beilstein Symposia address contemporary issues in the chemical and related sciences by employing an interdisciplinary approach. Scientists from a wide range of areas are invited to present aspects of their work for discussion, with the aim of not only advancing science, but also enhancing interdisciplinary communication. Traditionally, the Beilstein Symposia are kept small with up to 50 participants to provide a convivial atmosphere for the both lectures and lively discussions and the ready exchange of thoughts and ideas.

Over the past decade, the scientific community of post-proteomics and post-genomics witnessed the rapid evolution of a new scientific field – the glycomics. The investigation of both glycans and glycan-binding proteins and lipids revealed increasingly the role of complex carbohydrates in diverse inter- and intracellular processes. Advances in analytical technologies, carbohydrate chemistry and structural biology led to an increased understanding of the high degree of variability of both composition, structure and function of sugars. Additionally, structure-function studies showed an inherent complexity which is determined by different branching patterns, various possible linkage positions and numerous building blocks.

Even though there has been significant progress in the development of interdisciplinary approaches such as experimental and computer scientific tools, the general technological developments in glycomics lag behind those in the proteomic and genomic areas. In particular, despite the current progress in glyco-bioinformatics regarding the computational characterization of carbohydrates, the glycomics community is still lacking a systematic and comprehensive database and analysis software. The database landscape is made up of numerous independent and disconnected databases with partially overlapping core areas. These databases provide neither complete nor compatible data sets on glycan structures. Additionally, since the individual data encoding and analysis software tools do not use a common language for the representation of schematic structures and sequence topologies, data processing and interpretation become extremely challenging.

The underlying aim of this symposium is to bring together glycochemists and biologists with experts in bioinformatics and computer sciences to pave the way for a concerted effort in the area of glyco-bioinformatics. Scientists who ‘‘produce’’ data met those who ‘‘use’’ the data. They discussed aspects such as data mining, structure prediction and docking of carbohydrates, as well as web-based services to combine proteomics and glycomics data for structure-function research and glycosylation analysis. This meeting continued successfully the efforts resulting from the first symposium held in October 2009 to discuss the necessity of a uniform data reporting practice that supports biologists, chemists and all interested in glycosciences to enable the integration of their experimental and analysis data into glyco-bioinformatics platforms.

We would like to thank particularly the authors who provided us with written versions of the papers that they presented. Special thanks got to all those involved with the preparation and organization of the symposium, to the chairmen who piloted us successfully through the sessions and to the speakers and participants for their contribution in making this symposium a success.

Frankfurt/Main, July 2012

Martin Hicks,
Carsten Kettner,
Peter Seeberger

Glycoinformatics involves the development of computational methods and tools for the understanding of glycan function, including the development of databases, which use these methods and tools for validation of results. Thus several databases have been developed, storing a plethora of data from various analytical perspectives. These invaluable resources provide the data which theoretical computer scientists and data mining experts can use to develop new models and tools. This paper will describe the various carbohydrate-related databases that have become rather stable in this field, along with some of the methods that have been developed for analysing the glycan data from various perspectives. In particular, we focus on glycan biomarker and glycan binding pattern prediction.

The glycan chains of cellular glycoconjugates harbour information essential for many physiological processes. It can be decoded by counter-receptors. Among them, lectins (carbohydrate-binding proteins except antibodies, enzymes working on the cognate glycans and sensor/transport proteins for free sugars) play a prominent role in translating the sugar code. The exquisite precision, with which distinct glycoconjugates and lectins form pairs, poses the question on the underlying molecular mechanism(s) that guide(s) lectins to only few target sites (‘the needles in the haystack’), and this even with cell-type specificity. To provide a detailed concept and hereby give research a clear direction, structural characteristics on the side of the glycans are identified and systematically listed. As a result, a six-level scheme is devised, moving from sequence and shape to density of presentation, in glycoconjugates and membranes. It is flanked by an illustration of the range of modes for the topological display of binding sites in human lectins, via covalent and non-covalent clustering, to document the remarkable degree of sophistication reached within this recognition system. The discovery of orchestration of glycan display with presence of the matching effector in space and time and its functional consequences, e. g. to keep activated T effector cells under control preventing autoaggression or to drive pancreatic cancer cells into anoikis, sets examples of clinical relevance on how this concept is realized. In summary, the combination of sequence/shape and topology (e. g. local density of cognate sites, together with cross-linking capacity of lectins to elicit efficient post-binding signalling) appears to be the key for the understanding of molecular specificity. At the same time, it makes intricate dynamic regulation and perspectives for rational drug design possible. Figuring out the details is a challenge for interdisciplinary research involving fields from computational chemistry to molecular medicine.

The interpretation, evaluation, and reproduction of glycomics and glycoproteomics experiments are impeded by the failure to provide scientists who consume the results of these analyses with sufficient information describing the methods used to obtain the analytical data. With the enthusiastic support of glycoscientists and journal editors, a new initiative to specify the Minimum Information Required for A Glycomics Experiment (MIRAGE) has been established to address the unique data reporting aspects of glycoanalytic experiments. MIRAGE aims neither to dictate or control the experimental techniques used in a glyco-analysis nor to establish a metric for judging the quality of an experiment. Rather, it merely enumerates the information (data and metadata) that should be provided when the results of a glycoanalytic study are submitted to a journal or database.

Carbohydrates remain as one of the most challenging fields of study mostly due to the immense catalogue of carbohydrate structures that can be obtained as a direct result of their non-template dependent synthesis. Owing their chemical nature, there exist a huge number of potential combinations for glycostructures with different complexity which makes their synthesis difficult and almost impossible in most cases using only a traditional chemical synthesis approach. As glycans are involved in distinct physiological roles including energy
store, infection, pathogenesis and cell signalling among other processes, studies dealing with carbohydrates synthesis and regulation have increase within the last decades. Furthermore, carbohydrates as well as other glycosylated compounds including antioxidants, drugs and different proteins find application in the food and cosmetic industry as well as in health care, thus controlled glycosylation is targeted in order to develop new potential therapeutic agents as well as functional foods ingredients.
A strategy combining protein and substrates engineering as well as classical chemical synthesis has been necessary in order to achieve the synthesis of tailor-made oligosaccharides and glycostructures. Different approaches are described in this review regarding the control of chemo-, stereo- and regio-selectivity of carbohydrate active enzymes that successfully allowed the synthesis of an expanded spectrum of new glycostructures including those synthesized from non-natural substrates.

Many diarrhoeal diseases such as cholera are caused by protein toxins that have an AB₅ hetero-oligomeric structure. The proteins comprise a single toxic A-subunit and a pentameric B-subunit that interacts with specific cell surface glycolipids. Inhibitors of such protein-carbohydrate interactions could provide prophylactic treatments for these debilitating diseases. In our work we aim to understand the binding interactions of multivalent inhibitors for bacterial toxins. Often a single biophysical technique is limited in the information it can provide, whereas a more complete picture can be constructed through an integrated approach using a broad range of biophysical methods. For example, the importance of protein and ligand dynamics in multivalent interactions is revealed when combinations of NMR spectroscopy, isothermal titration calorimetry, analytical ultracentrifugation and dynamic light scattering are used to study to different multivalent systems.

The cell surface of most organisms is covered by carbohydrates linked to lipids or proteins. In gram-negative bacteria there are generally two kinds of carbohydrate molecules covering the cell surface; lipopolysaccharides (or occasionally lipooligosaccharides) and capsular polysaccharides. Whilst the capsular polysaccharides, when present, are very long and loosely attached to the cell surface the lipopolysaccharides are anchored in the cell membrane and protrude perpendicular to it. Thus, in absence of a capsule, the surface presented to other microbes and the immune system is dominated by the ends of the lipopolysaccharide molecules. Here we show that structures presented to the environment are shared among a wide range of different bacteria and can often be predicted from the chemical structure of the polymer.

MIT Technology Review considers glycomics to be one of the ten technologies with the capacity to change the world. Every class of major biomolecule identified so far either has a carbohydrate as a major constituent (e.g. 2-deoxyribose in DNA) or occurs also in a glycosylated form. Glycoproteins and glycolipids are key molecules involved in cell-cell interaction or cell-signalling, proteoglycans and glucosaminoglycans are crucial components of the animal extracellular matrix whereas certain carbohydrate polymers are important energy storage molecules. With the exception of DNA, the biosynthesis of the carbohydrate portion of biomolecules is not a template driven process but the result from concerted actions of numerous glycosyltransferases and glycosyl-donor synthesizing enzymes. These biosynthetic pathways provide the cell with the possibility to fine-tune particular features of glycosylated biomolecules without modifying the actual activity. The capacity to completely reverse IgG function has been shown for minor modifications in the IgG N-glycan structure. The addition of a single sialic acid molecule is able to convert IgG from being a pro-inflammatory into an anti-inflammatory agent and the addition of a core fucose residue the very same N-glycan can inhibit initiation of antibody-dependent cell cytotoxicity by obstructing its binding to the FcγRIIIa receptor without actually changing the actual binding properties towards its antigen...

Self-assembled monolayers (SAMs) on gold have become widely used as a platform for studying chemical and biochemical reactions, for studying biomolecular interactions and for the development of nanoscale devices. We have used this platform to study the solid-supported synthesis of carbohydrates and glycopeptides using both chemical and enzymatic methods. An attractive feature of the technology is the opportunity for miniaturisation and in situ analysis using mass spectrometry, SPR and fluorescence spectroscopy. Applications for the synthesis of complex oligosaccharides and glycopeptides to generate glycoarrays and their application in biology and medicine are discussed.

Glyco-bioinformatics is an emerging sub-field of bioinformatics, aiming to develop tools, databases, web services and workflows to facilitate research in the field of glycomics. Although glyco-bioinformatics is still in its infancy a large set of web applications, stand-alone applications and databases have been developed recently. Most of the programs are available via the Internet and can be used freely by glycoscientists. In the first half of this chapter we give a non-comprehensive overview of the tools that have been developed for the different subfields of glyco-bioinformatics. In the second section we discuss fundamental problems that hinder rapid progress in the field and identify milestones to be achieved in order to overcome these problems.

Carbohydrates provide a rich source of structural diversity that could be increasingly useful for innovative drug design. We suggest a representation of monosaccharides based on their pharmacophoric properties (pseudoreceptor model) to enable quantitative similarity searching with the aim to identify sugar bioisosters and functionally equivalent scaffolds for synthesis. We present a bioinformatical comparison of carbohydrate structures based on pseudoreceptor models. A similarity matrix was computed for 19 monosaccharide structures. As an outcome of this preliminary analysis, one might consider both glucose and deoxyribose as "universal" sugars with regard to their receptor interaction potential. Potential applications of pharmacophore feature representations of carbohydrate structures in bioinformatics are discussed. A recent case study is reviewed that led to the identification of aminoglycoside scaffold replacements with antibacterial potential by pseudoreceptor-based virtual screening of a large compound library.

Glycomimetics are valuable tools in glycobiology, suited to address the queries of glycomics. Since in glycomimetics the natural structural features of oligosaccharides have been altered in various ways, the nomenclature that is used to systematically describe structures and properties of naturally occurring sugar structures cannot be applied. An appropriate nomenclature is desirable. Moreover, it is necessary to understand the conformational properties that are displayed by – especially – multivalent glycomimetics. Molecular dynamics simulations using explicit solvent molecules are suited to obtain an impression of the conformational space occupied by various multivalent glycomimetics such as the glycodendrimers and so-called octopus glycosides. Unexpected similarities on one hand and discrepancies on the other hand have been shown by extensive modelling and can be correlated with the results of biological testing.

As in proteomics, the speed of the advances in glycomic discovery is dependent upon the development of a specific bioinformatic knowledgebase that links various forms of glycoanalytical data to repositories of known glycan structures. The UniCarbKB project (www.unicarbkb.org) is a partnership of leading international research groups come together in an effort to develop and provide an informatic framework for the storage of high-quality structural glycan collections including informative meta-data and annotated experimental datasets. UniCarbKB seeks to advance the integration of data capture and management within the glycomics discipline.

This paper describes the impact of cloud computing and the use of GPUs on the performance of Autodock and Gromacs respectively. Cloud computing was applicable to reducing the "tail" seen in running Autodock on desktop grids and the GPU version of Gromacs showed significant improvement over the CPU version. A large (200,000 compounds) library of small molecules, seven sialic acid analogues of the putative substrate and 8000 sugar molecules were converted into pdbqt format and used to interrogate the Trichomonas vaginalis neuraminidase using Autodock Vina. Good binding energy was noted for some of the small molecules (~-9 kcal/mol), but the sugars bound with affinity of less than -7.6 kcal/mol. The screening of the sugar library resulted in a "top hit" with α-2,3-sialyllacto-N-fucopentaose III, a derivative of the sialyl Lewis^x structure and a known substrate of the enzyme. Indeed in the top 100 hits 8 were related to this structure. A comparison of Autodock Vina and Autodock 4.2 was made for the high affinity small molecules and in some cases the results were superimposable whereas in others, the match was less good. The validation of this work will require extensive "wet lab" work to determine the utility of the workflow in the prediction of potential enzyme inhibitors.

Advance in bioinformatics has been substantially influenced by the management of biological data flows. In the most common –omics domains, such as genomics and proteomics, data quality and integration have raised questions and have solutions that can partially address the similar current predicament of glycomics data flows. Some lessons learnt from these can benefit the study of glycans at a time when high throughput data production is well underway.