Proceedings of the

Beilstein Bozen Symposium

Chemistry and Time

19 – 23 May 2014, Prien, Germany

The articles of the conference proceedings are published in Perspectives in Science and freely accessible.

Chemistry and Time

Martin G. Hicks and Carsten Kettner

Beilstein-Institut, Frankfurt am Main, Germany

The Beilstein Symposia address contemporary issues in chemistry and neighbouring sciences by emphasizing interdisciplinarity. Scientists from a wide range of areas – often outside chemistry – are invited to present aspects of their work for discussion with the aim not only to advance science, but also to enhance inter-disciplinary communication.

Temporal measurements of phenomena have been carried out continuously by natural scientists over the centuries. Time is the dimension used to order events from the past via the present to the future and is not reversible (even though mankind still dreams of time machines that enable travel into the past or future). This irreversibility is determined by thermodynamics, which describes the direction of events by the increase of entropy. For most people, the external “Zeitgeber” that regulate our biological rhythms combined with aging, reproduction, evolution and geology make time very real and directional. Time is relative and asymmetric – or isn’t it?

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Chemistry space-time

David A. Winkler

CSIRO Manufacturing Flagship, Clayton South 3169, Australia and
Monash Institute of Pharmaceutical Sciences, Parkville 3052, Australia

Most physical scientists are aware of the intimate relationship between space and time. Einstein quantified and clarified this relationship in the theories of General and Special Relativity. Space-time is a mathematical model that combines space and time into a single interwoven continuum. It combines space and time into a single manifold called Minkowski space, as opposed to the commonly experienced Euclidian space.

In cosmology, the concept of space-time combines space and time to a single abstract universe. Mathematically it is a manifold consisting of “events” which are described by some type of coordinate system. Typically three spatial dimensions (length, width, height), and one temporal dimension (time) are required.

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The logic of metabolism

Antoine Danchin and Agnieszka Sekowska

AMAbiotics SAS, Brain and Spine Institute, Hôpital de la Pitié-Salpêtrière, Paris, France

Metabolism is often perceived as a fairly haphazard intertwined collection of chemical compounds that needs to be memorised by heart. The apparent absence of logic in its organisation dissuades most investigators to enter its arcanes. Yet, metabolism, that results from highly selective constraints is logically organised. The atoms of life must build up stable covalent bonds. Symmetry breaking is the rule. Proteinogenic amino acids are of the l-enantiomer type, and this will imply that carbohydrates are of the d-type. Water is ubiquitous because it favours entropy-driven shaping of macromolecules. Then, being the bathing medium of life, hydrolysis is the driving force in orientating pathways. Phosphates, in water, are metastable towards hydrolysis, and this makes them the ultimate energy quantum and currency. Making a variety of reactive molecules in the same retort implies either compartmentalisation or a protection/deprotection procedure, as in the laboratory of all chemists.

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A brief history of circadian time: the e mergence of redox oscillations as a novel component of biological rhythms

Lisa Wulund and Akhilesh B. Reddy

Department of Clinical Neurosciences, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Circadian rhythms are present in all living organisms. They organise processes such as gene transcription, mitosis, feeding, and rest at different times of day and night. These rhythms are orchestrated by a network of core ‘clock genes’ that are organised into transcription-translation feedback loops (TTFLs), producing oscillations with a period of approximately 24 hours. The modern understanding of circadian timekeeping has revolved around the TTFL paradigm. Recently, however, this has been challenged by new findings that redox reactions persist in the absence of gene transcription, and that cycles of oxidation and reduction are conserved across all domain of life. These results suggest that non-transcriptional processes such as metabolic state may interact and work in parallel with the canonical genetic mechanisms of keeping circadian time.

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Sequestration of plant-derived glycosides by leaf beetles: a model system for evolution and adaptation

Wilhelm Boland

Max Planck Institute for Chemical Ecology, Jena, Germany

Leaf beetles have developed an impressive repertoire of toxins and repellents to defend themselves against predators. Upon attack, the larvae discharge small droplets from glandular reservoirs on their back. The reservoirs are “bioreactors” performing the late reactions of the toxin-production from plant-derived or de novo synthesised glucosides. The import of the glucosides into the bioreactor relies on a complex transport system. Physiological studies revealed a functional network of transporters guiding the glucosides through the larval body into the defensive system. The first of the involved transporters has been identified and characterised concerning selectivity, tissue distribution, and regulation. The development of a well-tuned transport system, perfectly adjusted to the compounds provided by the food plants, provides the functional basis for the leaf beetle defenses and their local adaptation to their host plants.

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Nutrient regulation of transcription and signaling by O-Glcnacylation


Gerald W. Hart

Department of Biological Chemistry, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

The cycling (addition and removal) of O-linked N-acetylglucosamine (O-GlcNAc) on serine or threonine residues of nuclear and cytoplasmic proteins serves as a nutrient sensor via the hexosamine biosynthetic pathway's production of UDP-GlcNAc, the donor for the O-GlcNAc transferase (OGT). OGT is exquisitely sensitive both in terms of its catalytic activity and by its specificity to the levels of this nucleotide sugar. UDP-GlcNAc is a major node of metabolism whose levels are coupled to flux through the major metabolic pathways of the cell. O-GlcNAcylation has extensive crosstalk with protein phosphorylation to regulate signalling pathways in response to flux through glucose, amino acid, fatty acid, energy and nucleotide metabolism.

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Simulating charge transport in flexible systems

Timothy Clark

Computer-Chemie-Centrum and Interdisciplinary Center for Molecular Materials, Department Chemie und Pharmazie, 
Excellence Cluster “Engineering of Advanced Materials”, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

Systems in which movements occur on two significantly different time domains, such as organic electronic components with flexible molecules, require different simulation techniques for the two time scales. In the case of molecular electronics, charge transport is complicated by the several different mechanisms (and theoretical models) that apply in different cases. We cannot yet combine time scales of molecular and electronic movement in simulations of real systems. This review describes our progress towards this goal.

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The transporter-mediated cellular uptake of pharmaceutical drugs is based on their metabolite-likeness and not on their bulk biophysical properties: Towards a systems pharmacology

Douglas B. Kell

School of Chemistry, Manchester Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM), and
The Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK

Several recent developments are brought together: (i) the new availability of a consensus, curated human metabolic network reconstruction (Recon2), approximately a third of whose steps are represented by transporters, (ii) the recognition that most successful (marketed) drugs, as well as natural products, bear significant similarities to the metabolites in Recon2, (iii) the recognition that to get into and out of cells such drugs hitchhike on the transporters that are part of normal intermediary metabolism, and the consequent recognition that for intact biomembrane Phospholipid Bilayer diffusion Is Negligible (PBIN), and (iv) the consequent recognition that we need to exploit this and to use more phenotypic assays to understand how drugs affect cells and organisms. I show in particular that lipophilicity is a very poor predictor of drug permeability, and that we need to (and can) bring together our knowledge of both pharmacology and systems biology modelling into a new systems pharmacology.

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Euglena in time: Evolution, control of central metabolic processes and multi-domain proteins in carbohydrate and natural product biochemistry

Ellis C. O’Neill1 and Robert A. Field2

1Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich, UK

2Department of Plant Sciences, University of Oxford, Oxford, UK

Euglena gracilis is a eukaryotic microalgae that has been the subject of scientific study for hundreds of years. It has a complex evolutionary history, with traces of at least four endosymbiotic genomes and extensive horizontal gene transfer. Given the importance of Euglena in terms of evolutionary cell biology and its unique taxonomic position, we initiated a de novo transcriptome sequencing project in order to understand this intriguing organism. By analysing the proteins encoded in this transcriptome, we can identify an extremely complex metabolic capacity, rivalling that of multicellular organisms. Many genes have been acquired from what are now very distantly related species. Herein we consider the biology of Euglena in different time frames, from evolution through control of cell biology to metabolic processes associated with carbohydrate and natural products biochemistry.

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Controlling time scales for electron transfer through proteins

Scot Wherland1 and Israel Pecht2

1Department of Chemistry, Washington State University, Pullman, Washington, USA

2Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

Electron transfer processes within proteins constitute key elements in biological energy conversion processes as well as in a wide variety of biochemical transformations. Pursuit of the parameters that control the rates of these processes is driven by the great interest in the latter reactions. Here, we review a considerable body of results emerging from investigation of intramolecular electron transfer (ET) reactions in two types of proteins, all done by the use of the pulse-radiolysis method: First are described results of extensive studies of a model system, the bacterial electron mediating protein azurin, where an internal ET between the disulfide radical ion and the Cu(II) is induced. Impact of specific structural changes introduced into azurin on the reaction rates and the parameters controlling it are discussed. Then, the presentation is extended to results of investigations of intra-protein ET reactions that are part of catalytic cycles of multi-copper containing enzymes. Again, the rates and the parameters controlling them are presented and discussed in the context of their efficacy and possible constraints set on their evolution.

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Soft nanomaterials analszed by in situ liquid TEM: Towards high resolution characterisation of nanoparticles in motion

Joseph P. Patterson, Maria T. Proetto, Nathan Gianneschi

Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA

In this article we present in situ transmission electron microscopy (TEM) of soft, synthetic nanoparticles with a comparative analysis using conventional TEM methods. This comparison is made with the simple aim of describing what is an unprecedented example of in situ imaging by TEM. However, we contend the technique will quickly become essential in the characterisation of analogous systems, especially where dynamics are of interest in the solvated state. In this case, particles were studied which were obtained from the direct polymerisation of an oxaliplatin analog, designed for an ongoing program in novel chemotherapeutic delivery systems. The resulting nanoparticles provided sufficient contrast for facile imaging in situ, and point toward key design parameters that enable this new characterisation approach for organic nanomaterials. We describe the preparation of the synthetic nanoparticles together with their characterisation in liquid water. Finally, we provide a future perspective of this technique for the analysis of soft and dynamic nanomaterials and discussion the progress which needs to be made in order to bring in situ liquid TEM to its full potential.

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Time flies like an arrow; fruit flies like bananas

Athel Cornish-Bowden

CNRS-BIP, Aix-Marseille Université, Marseille, France

The 2014 Beilstein Bozen Symposium on Chemistry and Time was as diverse in topics, and hence as difficult to summarise in a few words, as all of its predecessors. We can all agree, however, that time is fundamental in all of science, affecting everything we do, and everything that happens in a chemical system, and so the diversity of topics is just a reflection of reality, and the Symposium in Prien left all of its participants with the feeling that they had learned something interesting and novel.

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