Proceedings of

the Beilstein Bozen Symposium

Systems Chemistry

26 – 30 May 2008, Bolzano, Italy

The articles of the conference proceedings are available in PDF format.

Download the complete proceedings book in PDF format (43 MB).


The Beilstein symposia address contemporary issues in the chemical and related sciences by employing an interdisciplinary approach. Scientists from a wide range of areas – often outside chemistry – are invited to present aspects of their work for discussion with the aim of not only advancing science, but also, furthering interdisciplinary communication.

Chemistry and biology are two of the most creative sciences. The ability of chemists to design and create their own research objects is a unique feature of this science, bringing it close to art. The aesthetics of symmetry, of biomolecules, or of an elegant synthesis, dissolve the boundaries between art and science. The unique art of biological systems, often unrivalled in the degrees of scale, regularly provides inspiration for chemists and biologists striving for a greater understanding of nature.

Understanding of chemical and biological systems has often been best achieved through reductionism; the bottom-up approach in going from small reaction systems to more complex systems consisting of hundreds or thousands of components is usually impractical. Complex problems are broken down into smaller parts, on the assumption that these behave in predictable, reproducible ways so that new theories or methods can be developed, tested and refined. For example, chemistry has been used very creatively to help understand pharmacological systems. Modern biology through point mutations, siRNA, cloning and knockouts, also provides many creative tools to allow many insights into complex biological systems.

An underlying theme of the symposium was the quest to increase our understanding of nature going from methodologies with regard to chemical building blocks, to complex molecules, supramolecular assemblies, cells and organisms.

Complex chemical systems are, of course, not only biological in nature; comprehension of the underlying chemistry, in particular at the nano or meso-scale, of molecular organization allows a systems science approach to be applied to chemistry. Now that biologists and chemists are becoming able to modify and control biological systems, using the combined creativity and prowess of both disciplines, many hidden secrets of the biological systems in cells and organisms can be begun to be understood and investigated in a structured manner. The many parallels between contemporary chemistry and complex biological processes are resulting in innovative research projects throughout the world.

The secluded setting of Hotel Schloss Korb and its convivial atmosphere provided once again the ideal location for the symposium and the ready exchange of thoughts and ideas. Of course, despite the great efforts of all participants, not all scientific problems could be solved over the three days, but many very interesting discussions were initiated which continued well after the symposium; we will be watching the evolution of systems chemistry with much interest over the next years.

We would like to thank particularly the authors who provided us with written versions of the papers that they presented. Special thanks go 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, March 2009
Martin G. Hicks
Carsten Kettner

Frustration: Physico-Chemical Prerequisites for the Construction of a Synthetic Cell

Antoine Danchin and Agnieszka Sekowska

Genetics of Bacterial Genomes – CNRS, Paris.

To construct a synthetic cell we need to understand the rules that permit life. A central idea in modern biology is that in addition to the four entities making reality, matter, energy, space and time, a fifth one, information, plays a central role. As a consequence of this central importance of the management of information, the bacterial cell is organised as a Turing machine, where the machine, with its compartments defining an inside and an outside and its metabolism, reads and expresses the genetic program carried by the genome. This highly abstract organisation is implemented using concrete objects and dynamics, and this is at the cost of repeated incompatibilities (frustration), which need to be sorted out by appropriate «patches». After describing the organisation of the genome into the paleome (sustaining and propagating life) and the cenome (permitting life in context), we describe some chemical hurdles that the cell as to cope with, ending with the specific case of the methionine salvage pathway.

Catalysis at the Origin of Life Viewed in the Light of the (M,R)-Systems of Robert Rosen

Athel Cornish-Bowden and María Luz Cárdenas

Unité de Bioénergétique et Ingénierie des Protéines, CRNS, Marseilles.

Living systems as we know them today are both complex, displaying emergent properties, and extremely complicated, with huge numbers of different components. At the origin of life they must also have had emergent properties, and hence must have been complex, but they cannot have been as complicated as modern organisms, because we cannot imagine that the first organisms started with anything as elaborate as a ribosome and all of the protein-synthesis machinery. Understanding how complexity could arise in even the simplest early organism requires, however, a theory of life, something that is largely lacking from modern biology. Various authors have contributed elements of such a theory, and the (M,R)-systems of Robert Rosen provide a convenient starting point.

New Concepts for Catalysis

Corinna M. Reisinger, Subhas Chandra Pan and Benjamin List

Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany.

Organocatalysis, the catalysis with low-molecular weight catalysts where a metal is not part of the catalytic principle, can be as efficient and selective as metal- or biocatalysis. Important discoveries in this area include novel Lewis base-catalyzed enantioselective processes and, more recently, simple Brønsted acid organocatalysts that rival the efficiency of traditional metal-based asymmetric Lewis acid-catalysts. Contributions to organocatalysis from our laboratories include several new and broadly useful concepts such as enamine catalysis and asymmetric counteranion directed catalysis. Our lab has discovered the proline-catalyzed direct asymmetric intermolecular aldol reaction and introduced several other organocatalytic reactions.

New Tools for Molecule Makers:
Emerging Technologies

Steven V. Ley and Ian R. Baxendale

Department of Chemistry, University of Cambridge.

If one reflects for a moment about the current practices used by a skilled synthesis chemist, we must be impressed by the sheer complexity of what can be achieved. Moreover, the impact on society is staggering, given the array of healing drugs, compounds that protect and guarantee our food supply to the colours and materials of our modern society. All the sciences benefit to some degree from our ability to assemble novel molecular architectures that display function and beneficial properties. The synthesis chemist’s ability to understand and create these selective features at a molecular level from simple building blocks is truly awe-inspiring; especially given that a combination of only a small selection of nine different elements of the periodic table and a molecular weight limit of 500 Daltons can, in principle, generate a difficult to comprehend number of 1063 different molecules! Despite the obvious achievements of chemical synthesis, it is not without its problems. These relate to its current sustainability as a discipline, where we see issues of poor atom and step economy. [...] In our work we have concentrated on the use of immobilised reagents and scavenging methods for multi-step molecular synthesis and shown how powerful these concepts can be in the construction of pharmaceutical agents and natural products. Indeed, it is this holistic systems chemistry approach that differentiates this from more conventional synthesis planning. In this lecture we discuss how these immobilisation methods for reagents, scavengers and catch-and-release techniques can be combined with phase switching and controlled release techniques to achieve chemical synthesis by continuous processing in the flow mode. This will necessitate the development of suitable microreactors, packed flow tubes, flow coils, microfluidic reactor chips and appropriate reaction engineering. In order to maintain flexibility and reconfiguration of the equipment, modular units will be preferred. User-friendly interfaces and ease of operation are also important components, and although we recognise that this will represent a change in technology, it will constitute a massive change in synthesis philosophy.

Microreactors as the Key to the Chemistry Laboratory of the Future

Karolin Geyer and Peter H. Seeberger

Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH) Zurich.

The aim of synthetic chemists and the chemical industry is to perform chemical transformations in a highly efficient and environmentally benign manner. This involves atom economy and atom efficiency of the particular reactions on one hand; on the other hand it includes aspects of the reaction performance such as process safety, solvent and reagent consumption, and purification procedures. A well-engineered approach to elegantly overcome some of the aspects related to process performance is the use of continuous-flow microfluidic devices in chemical laboratories. This chapter highlights some application of these new tools in synthetic laboratories and how continuous-flow reactors may change the way chemists will perform their research in the future.

Chemical Biology with Organometallics

Eric Meggers

Fachbereich Chemie, Philipps-Universität Marburg.

Inorganic and organometallic moieties are explored as structural scaffolds for the design of biologically active compounds. In this strategy, a metal center plays a structural role by organizing the organic ligands in the three-dimensional receptor space. It is hypothesized that this approach allows to access unexplored chemical space, thus giving new opportunities for the design of small molecules with unprecedented biological properties. Along these lines, our group pioneered the design of organometallic scaffolds for the inhibition of protein kinases. These compounds are formally derived from the class of ATP-competitive indolocarbazole alkaloids and allow to access novel structures with very defined and rigid shapes in an economical fashion, having resulted in the discovery of picomolar inhibitors for protein kinases with impressive selectivity profiles. This article summarizes the most important results over the last few years.

Modelling for Regenerative Medicine:
Systems Biology Meets Systems Chemistry

David A. Winkler, Julianne D. Halley and Frank R. Burden

CSIRO Molecular and Health Technologies, Clayton, Australia.

Complex systems science is making substantial contributions to the study of biological systems, and has made a substantial contribution to the new field of systems biology. Systems biology focuses on the systematic study of complex interactions in biological systems using an integrative rather than reductionist perspective. One of the goals of systems biology is to study, model, and understand new emergent properties of biological systems from a complex systems perspective. This integrative approach to biology is generating substantial benefits in facilitating study of larger more complicated systems, providing improved understanding of nonlinear system properties, and provides an ability to model systems at appropriate levels of detail where the model is matched to data density and research questions. Various aspects of systems biology have been reviewed recently. Chemistry has lagged behind most other disciplines in adopting complex systems approaches, possibly because it has largely been a reductionist science, and reductionist approaches have been very successful. Adopting a complementary complex systems approach
to chemistry will build on this success to study more complex matter.

The Cellular Uptake of Pharmaceutical Drugs is Mainly Carrier-mediated and is thus an Issue not so Much of Biophysics but of Systems Biology

Douglas B. Kell and Paul D. Dobson

School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester.

It is widely believed that most drug molecules are transported across the phospholipid bilayer portion of biological membranes via passive diffusion at a rate related to their lipophilicity (expressed as log P, a calculated c log P or as log D, the octanol:water partition coefficient). However, studies of this using purely phospholipid bilayer membranes have been very misleading since transfer across these typically occurs via the solvent reservoirs or via aqueous pore defects, neither of which are prevalent in biological cells. Since the types of biophysical forces involved in the interaction of drugs with lipid membranes are no different from those involved in their interaction with proteins, arguments based on lipophilicity also apply to drug uptake by membrane transporters or carriers. A similar story attaches to the history of mechanistic explanations of the mode of action of general anaesthetics (narcotics). Carrier-mediated and active uptake of drugs is far more common than is usually assumed. This has considerable implications for the design of libraries for drug discovery and development, as well as for chemical genetics/genomics and systems chemistry.

The Chemistry of Signal Transduction in the
TetR System

Harald Lanig and Timothy Clark

Computer-Chemie-Centrum, Friedrich-Alexander Universität Erlangen-Nürnberg.

Signal transduction proteins in biological systems must be very flexible to undergo the allosteric changes necessary for their function. It is current practice to investigate the modes of action of these systems by X-ray spectroscopy of the different states trapped as crystals. Unfortunately, the forces acting on the proteins by packing effects may lead to distortions comparable to the changes that occur during the allosteric movements. This makes it questionable as to whether X-ray structures can be used to deduce induction mechanisms. In this work, we show for DNA-binding tetracycline repressor proteins that molecular dynamics simulations offer an interesting alternative for determining the induction state and possible mechanisms switching between them. Based on data sampled for different repressor classes with several force field parameter sets, we show that MD simulations have convincing advantages over the analysis of static structures influenced by crystal packing.

Protein Interaction, Association and Fibrillation

Sara Linse

Department of Biophysical Chemistry, Lund University.

A protein can fold efficiently with high fidelity if on average native contacts survive longer than non-native ones. If native contacts survive long enough to obtain a certain level of probability that other native contacts form before the first interacting unit dissociates this provides the folding process with directionality towards the native state and no particular pathway is needed. Interactions among hydrophobic residues are by far more important than electrostatic interactions in protein assembly, folding and stability. Proteins may under certain conditions and as a function of time give up their native folded state and form amyloid fibrils – a process that is involved in a number of human diseases. The fibrillation process can be perturbed by the presence of foreign surfaces, for example nanoparticles of different surface character.

Shedding Light on Nucleic Acids and DNA under Construction

Alexander Heckel

Cluster of Excellence Macromolecular Complexes, University of Frankfurt.

The first part of our research deals with the spatiotemporal regulation of biological processes. We use light as addressing mechanism and modify nucleic acids in a way to make them light-responsive. Light has the advantage that it can be easily generated and manipulated with well-established (laser and microscope) technologies and many of the currently investigated model organisms are light-accessible. On the other hand nucleic acids are the base of powerful techniques such as for example RNA interference for the regulation of genes and aptamers for the regulation of the function of proteins.

In the second part of our research we are exploring new ways to assemble nanometer-scaled objects from DNA but instead of only relying on the Watson-Crick interaction we are using alternative – orthogonal – interaction strategies like for example ‘‘Dervan-type polyamides’’ which can sequence-selectively bind to double-stranded DNA. Two of these polyamides – combined via a linker – form a ‘‘DNA strut’’ which can sequence-selectively ‘‘glue’’ together two DNA double helices.

High-throughput Analysis of Nucleoside and Nucleotide-binding by Proteins

Justin K.M. Roberts1, Cecelia Webster1, Thomas C. Terwilliger2 and Chang-Yub Kim2

1Department of Biochemistry, University of California.
2Bioscience Division, Los Alamos National Laboratory, USA.

Many proteins function via selective binding of small molecules, and an important class of ligands is nucleosides, including derivative mono- and dinucleotides, which participate in processes such as catalysis and signal transduction. Determining the specificity of nucleoside/nucleotide binding is therefore central to understanding the function of many proteins. We describe use of dye-ligand affinity chromatography methods to identify putative nucleotide-binding proteins, and to determine the specificity of binding to structurally related ligands. In one approach, putative nucleoside-binding proteins are captured from crude protein extracts of cells, for identification via standard proteomic methods. In a second approach, interactions of different nucleosides with purified recombinant protein targets, immobilized on dye, are determined to assess the specificity of ligand recognition by a given nucleotide-binding protein in the context of structural and functional genomics, and drug development.

Systems Biology from Chemical Combinations

Joseph Lehár1,2, Andrew Krueger2, Grant Zimmermann1 and Alexis Borisy1

1CombinatoRx Incorporated, Cambridge, U.S.A.
2Boston University Bioinformatics/Bioengineering, U.S.A.

Systematic testing of chemical combinations in cell-based disease models can yield novel information on how proteins interact in a biological system, and thus can make important contributions to biological models of those diseases. Such combination screens can also preferentially discover synergies with beneficial therapeutic selectivity, especially when used in high-order mixtures of more than two agents. These studies demonstrate the value obtainable from combination chemical genetics, and reinforce the growing realization that the most useful paradigm for a drug target is no longer a single molecule in a relevant pathway, but instead the set of targets that can cooperate to produce a therapeutic response with reduced side effects.

A Dynamical Supramolecular System for Medicinal Chemistry – A Step Towards Contiguous Chemical Spaces

Holger Wallmeier1, Norbert Windhab2 and Gerhard Quinkert3

1Sulzbach/Taunus, Germany.
2Evonik Röhm GmbH, Darmstadt, Germany.
3Institut für Organische Chemie und Chemische Biologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main.

A system based on pyranosyl-RNA (pRNA), a molecular scaffold which is able to self-assemble by Watson-Crick-like base pairing is presented. Molecular entities of very different types can be linked covalently to the components of the self-assembly scaffold to form conjugates which can be used in medicinal chemistry. Sets of conjugates with each of the different scaffold components define sublibraries for supramolecular assembly. Combining conjugates from different sublibraries, new (supra-)molecular entities with new properties can be formed by self-assembly in a systematic way. The supramolecular nature and the equilibrium of reversible self-assembly of the system ensure its dynamical behavior. In the presence of a molecular receptor, a complex system of equilibria exists, which allows controlling of the entire system. The dynamical properties of the system enable contiguous adaptation to changes of the conditions and offer new perspectives in obtaining structure/activity relationships.

‘‘Promiscuous’’ Ligands and Targets Provide Opportunities for Drug Design

Gisbert Schneider1 and Petra Schneider2

1Johann Wolfgang Goethe-Universität, Frankfurt am Main.
2 Schneider Consulting GbR, Oberursel, Germany.

Flexibility, structural adaptability and non-selective pharmacophoric features of ligands and macromolecular receptors are major challenges in molecular design. These properties can lead to promiscuous binding behavior and often prevent modeling of reasonable structure-activity relationships. We have analyzed neighborhood behavior of bioactive ligands and protein binding pockets in terms of molecular shape and pharmacophoric features. It turned out that there exist certain relationships between the shape and the buriedness of a protein pocket and its ability to accommodate a small molecule ligand. The self-organizing map concept and clustering techniques is presented as a means for predicting potential bioactivities of ligands, and ‘‘de-orphanizing’’ of drugs and receptor proteins. Opportunities for ‘‘scaffold-hopping’’ and ‘‘re-purposing’’ are discussed in the context of systems chemistry.