Maps, books and other metaphors for systems biology

We briefly review the use of metaphors in science and progressively focus on fields from biology and molecular biology to genomics and bioinformatics. We discuss how metaphors are both a tool for scientific exploration and a medium for public communication of complex subjects, by various short examples. Finally, we propose a metaphor for systems biology that provides an illuminating perspective for the ambitious goals of this field and delimits its current agenda.     

Exploring the Conformational Behavior of Rigid Porphyrin-Quinone Systems by High-Temperature MD Simulations and Temperature-Dependent 1H-NMR Experiments

Photoinduced electron transfer reactions play an important role in the primary step of the biological photosynthesis process. In an attempt to understand better the mechanism of the charge separation organic donor-acceptor molecules containing porphyrins and quinones were designed as photosynthesis models. In order to study the structure dependence of the photoinduced electron transfer twofold and fourfold bridged porphyrin-quinone systems with increasing donor-acceptor distance were synthesized (Figure 1) [1, 2, 3]. It was assumed that in these molecules the porphyrin and quinone should be linked in a rigid and well-defined orientation. To verify this assumption the conformational behavior of these systems was studied by high-temperature MD simulations in combination with conformational analysis of selected minimized structures [4, 5].     

Protein oxidation at the air-lung interface

Summary. Whilst performing its normal functions the lung is required to deal with a range of toxic insults. Whether these are infectious agents, allergens or air pollutants they subject the lung to a range of direct and indirect oxidative stresses. In many instances these challenges lead to oxidative alterations of peptides and proteins within the lung. Measurement of protein oxidation products permits the degree of oxidative stress to be assessed and indicates that endogenous antioxidant defences are overwhelmed. The range of protein oxidation products observed is diverse and the nature and extent of specific oxidation products may inform us about the nature of the damaging ROS and NOS. Recently, there has been a significant shift away from the measurement of these oxidation products simply to establish the presence of oxidative stress, to a focus on identifying specific proteins sensitive to oxidation and establishing the functional consequences of these modifications. In addition the identification of specific enzyme systems to repair these oxidative modifications has lead to the belief that protein function may be regulated through these oxidation reactions. In this review we focus primarily on the soluble protein components of within the surface liquid layer in the lung and the consequence of their undue oxidation.     

Molecular interaction networks for the analysis of human disease: Utility,limitations, and considerations

High‐throughput ‘‐omics’ data can be combined with large‐scale molecular interaction networks, for example, protein–protein interaction networks, to provide a unique framework for the investigation of human molecular biology. Interest in these integrative ‘‐omics’ methods is growing rapidly because of their potential to understand complexity and association with disease; such approaches have a focus on associations between phenotype and “network‐type.” The potential of this research is enticing, yet there remain a series of important considerations. Here, we discuss interaction data selection, data quality, the relative merits of using data from large high‐throughput studies versus a meta‐database of smaller literature‐curated studies, and possible issues of sociological or inspection bias in interaction data. Other work underway, especially international consortia to establish data formats, quality standards and address data redundancy, and the improvements these efforts are making to the field, is also evaluated. We present options for researchers intending to use large‐scale molecular interaction networks as a functional context for protein or gene expression data, including microRNAs, especially in the context of human disease.     

The Interactorium: Visualising proteins,complexes and interaction networks in a virtual 3‐D cell

Here, we describe the Interactorium, a tool in which a Virtual Cell is used as the context for the seamless visualisation of the yeast protein interaction network, protein complexes and protein 3‐D structures. The tool has been designed to display very complex networks of up to 40 000 proteins or 6000 multiprotein complexes and has a series of toolboxes and menus to allow real‐time data manipulation and control the manner in which data are displayed. It incorporates new algorithms that reduce the complexity of the visualisation by the generation of putative new complexes from existing data and by the reduction of edges through the use of protein “twins” when they occur in multiple locations. Since the Interactorium permits multi‐level viewing of the molecular biology of the cell, it is a considerable advance over existing approaches. We illustrate its use for Saccharomyces cerevisiae but note that it will also be useful for the analysis of data from simpler prokaryotes and higher eukaryotes, including humans. The Interactorium is available for download at http://www.interactorium.net .     

Systems biology,emergence and antireductionism

This study explores the conceptual history of systems biology and its impact on philosophical and scientific conceptions of reductionism, antireductionism and emergence. Development of systems biology at the beginning of 21st century transformed biological science. Systems biology is a new holistic approach or strategy how to research biological organisms, developed through three phases. The first phase was completed when molecular biology transformed into systems molecular biology. Prior to the second phase, convergence between applied general systems theory and nonlinear dynamics took place, hence allowing the formation of systems mathematical biology. The second phase happened when systems molecular biology and systems mathematical biology, together, were applied for analysis of biological data. Finally, after successful application in science, medicine and biotechnology, the process of the formation of modern systems biology was completed.Systems and molecular reductionist views on organisms were completely opposed to each other. Implications of systems and molecular biology on reductionist–antireductionist debate were quite different. The analysis of reductionism, antireductionism and emergence issues, in the era of systems biology, revealed the hierarchy between methodological, epistemological and ontological antireductionism. Primarily, methodological antireductionism followed from the systems biology. Only after, epistemological and ontological antireductionism could be supported.     

The crystal structure of Bombyx mori silk fibroin at the air–water interface

A new crystalline polymorph of Bombyx mori silk, which forms at the air–water interface, has been characterized. A previous study found this structure to be trigonal, and to be distinctly different than the two previously observed silk crystal structures, silk I and silk II. This new structure was named silk III. Identification of this new silk polymorph was based on evidence from transmission electron microscopy and electron diffraction, coupled with molecular modeling. In the current paper, additional data enables us to refine our model of the silk III structure. Some single crystal electron diffraction patterns indicate a deviation in symmetry away from a perfect trigonal unit cell to monoclinic unit cell. The detailed shape of the powder diffraction peaks also supports a monoclinic cell. The monoclinic crystal structure has an nonprimitive unit cell incorporating a slightly distorted hexagonal packing of silk molecular helices. The chains each assume a threefold helical conformation, resulting in a crystal structure similar to that observed for polyglycine II, but with some additional sheet-like packing features common to the threefold helical crystalline forms of many glycine-rich polypeptides. © 1997 John Wiley & Sons, Inc. Biopoly 42: 705–717, 1997     

Molecular characterization of the immune system: emergence of proteins,processes, and domains

Many genes and proteins are required to carry out the processes of innate and adaptive immunity. For many studies, including systems biology, it is necessary to have a clear and comprehensive definition of the immune system, including the genes and proteins that take part in immunological processes. We have identified and cataloged a large portion of the human immunology-related genes, which we call the essential immunome. The 847 identified genes and proteins were annotated, and their chromosomal localizations were compared to the mouse genome. Relation to disease was also taken into account. We identified numerous pseudogenes, many of which are expressed, and found two putative new genes. We also carried out an evolutionary analysis of immune processes based on gene orthologs to gain an overview of the evolutionary past and molecular present of the human immune system. A list of genes and proteins were compiled. A comprehensive characterization of the member genes and proteins, including the corresponding pseudogenes is presented. Immunome genes were found to have three types of emergence in independent studies of their ontologies, domains, and functions. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Global spread of helminth parasites at the human–domestic animal–wildlife interface

Changes in species distributions open novel parasite transmission routes at the human–wildlife interface, yet the strength of biotic and biogeographical factors that prevent or facilitate parasite host shifting are not well understood. We investigated global patterns of helminth parasite (Nematoda, Cestoda, Trematoda) sharing between mammalian wildlife species and domestic mammal hosts (including humans) using >24,000 unique country‐level records of host–parasite associations. We used hierarchical modelling and species trait data to determine possible drivers of the level of parasite sharing between wildlife species and either humans or domestic animal hosts. We found the diet of wildlife species to be a strong predictor of levels of helminth parasite sharing with humans and domestic animals, followed by a moderate effect of zoogeographical region and minor effects of species’ habitat and climatic niches. Combining model predictions with the distribution and ecological profile data of wildlife species, we projected global risk maps that uncovered strikingly similar patterns of wildlife parasite sharing across geographical areas for the different domestic host species (including humans). These similarities are largely explained by the fact that widespread parasites are commonly recorded infecting several domestic species. If the dietary profile and position in the trophic chain of a wildlife species largely drives its level of helminth parasite sharing with humans/domestic animals, future range shifts of host species that result in novel trophic interactions may likely increase parasite host shifting and have important ramifications for human and animal health.     

Multiscale model of CRISPR-induced coevolutionary dynamics: diversification at the interface of Lamarck and Darwin

The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) system is a recently discovered type of adaptive immune defense in bacteria and archaea that functions via directed incorporation of viral and plasmid DNA into host genomes. Here, we introduce a multiscale model of dynamic coevolution between hosts and viruses in an ecological context that incorporates CRISPR immunity principles. We analyze the model to test whether and how CRISPR immunity induces host and viral diversification and the maintenance of many coexisting strains. We show that hosts and viruses coevolve to form highly diverse communities. We observe the punctuated replacement of existent strains, such that populations have very low similarity compared over the long term. However, in the short term, we observe evolutionary dynamics consistent with both incomplete selective sweeps of novel strains (as single strains and coalitions) and the recurrence of previously rare strains. Coalitions of multiple dominant host strains are predicted to arise because host strains can have nearly identical immune phenotypes mediated by CRISPR defense albeit with different genotypes. We close by discussing how our explicit eco-evolutionary model of CRISPR immunity can help guide efforts to understand the drivers of diversity seen in microbial communities where CRISPR systems are active.     

Opportunities at the interface of chemistry and biology

The combination of the tools and principles of chemistry, together with the tools of modern molecular biology, allow us to create complex synthetic and natural molecules, and processes with novel biological, chemical and physical properties. This article illustrates the tremendous opportunity that lies at this interface of chemistry and biology by describing a number of examples, ranging from efforts to expand the genetic code of living organisms to the use of combinatorial methods to generate biologically active synthetic molecules.     

Opportunities at the interface of chemistry and biology

The combination of the tools and principles of chemistry, together with the tools of modern molecular biology, allow us to create complex synthetic and natural molecules, and processes with novel biological, chemical and physical properties. This article illustrates the tremendous opportunity that lies at this interface of chemistry and biology by describing a number of examples, ranging from efforts to expand the genetic code of living organisms to the use of combinatorial methods to generate biologically active synthetic molecules.     

Molecular dynamics of lipid association at the hydrophobic interface of gramicidin S

Gramicidin S was incorporated into dimyristoylphosphatidylcholine dispersions and the observed two-component EPR spectra of spin-labelled lipids at 30 °C were analysed by a two-stage algorithm, including spectral subtractions and two-site exchange simulations. A limited range of temperatures around 30 °C was found suitable for such measurements. It has been found that negatively charged labelled lipids display a selectivity towards the intramembranous part of the peptide. The relative association constants for spin-labelled stearic acid (14-SASL) and phosphatidylserine (14-PSSL) were K _r = 2.08± 0.10 and 1.18±0.08, respectively, when compared with the zwitterionic phosphatidylcholine label (14-PCSL, K _r≡ 1). The lateral diffusion of spin-labelled lipids in peptide-free regions causes exchange between those labels in the bulk fluid lipid phase and motionally restricted boundary labelled lipids at the apolar interface of gramicidin S. Owing to exchange, the spectral anisotropy of labelled lipids giving rise to the slow-motion spectral component was gradually decreased, and there was an augmentation of spectral intensity in between the motionally restricted (slow motion) and the fast tumbling (motionally averaged) labelled lipid components. Two-component exchange simulations allowed the determination of off-rates of labelled phospholipids, showing an inverse proportionality with lipid-protein selectivity. Spin-labelled procaine exhibited limited selectivity and fast exchange similar to the on-coming non-specifically associated lipids. Received: 25 May 1998 / Revised version: 14 September 1998 / Accepted: 5 November 1998     

Computer simulations of extractant primary amine N1923 and N1923 hydrochloride salt at water/chloroform interface

A molecular dynamics (MD) simulation has been carried out to investigate the structural and dynamical properties of extractant methyloctadecyl amine (N1923), and its hydrochloride salt at water/chloroform interface. The simulation results show that both N1923 molecule and protonated N1923 ion can self-assembly form a monolayer at the interface like most non-ionic or cationic surfactants. It is not only observed that the headgroup N atom of protonated N1923 ion arranges more tightly and orderly than that of N1923 molecule but also verified that the protonated headgroup of N1923 ion has stronger hydration ability than the polar headgroup of N1923 molecule.     

Edge effects on ground beetles at the woodlot–field interface are short‐range and asymmetrical

• 1 Boundaries between woodlots and agricultural habitats are numerous in temperate agricultural landscapes and influence ecological processes in both woodlots and agricultural habitats.
• 2 We aimed to determine how far the species assemblage of ground beetles in woodlot and open habitats was influenced by the presence of the woodlot–field boundary.
• 3 We studied the distribution of ground beetles on both sides of the boundaries of four woodlots along transects of pitfall traps (n = 140). The depth of edge influence (i.e. the distance from the boundary at which the presence of the boundary has no more significant influence) on the species assemblage of ground beetles in each woodlot and in each agricultural habitat was determined with nonlinear canonical analysis of principal coordinates, an ordination method that is followed by nonlinear regression of the principal coordinates on distance from the boundary.
• 4 The depth of edge influence on the species assemblages of ground beetles was asymmetrical relative to the boundary: it was generally higher and had higher variability in open habitats (14.4 ± 12.3 m) than in woodlots (4.9 ± 2.3 m). Species assemblages of ground beetles in edges were a mix between both adjacent species assemblages. Edge effects in woodlots were deeper in the woodlots exhibiting a deeper penetration of open habitat species. Symmetrically, edge effects in open habitat were deeper in the open habitats with a deeper diffusion of forest species into the open habitat.
• 5 Forest ground beetles were not threatened by edge effects. Rather, edge effects are likely to benefit agriculture, mostly through the dispersal of predatory forest species into agricultural fields.

     

Analysis of the interactome of ribosomal protein S19 mutants

Diamond–Blackfan anemia, characterized by defective erythroid progenitor maturation, is caused in one‐fourth of cases by mutations of ribosomal protein S19 (RPS19), which is a component of the ribosomal 40S subunit. Our previous work described proteins interacting with RPS19 with the aim to determine its functions. Here, two RPS19 mutants, R62W and R101H, have been selected to compare their interactomes versus the wild‐type protein one, using the same functional proteomic approach that we employed to characterize RPS19 interactome. Mutations R62W and R101H impair RPS19 ability to associate with the ribosome. Results presented in this paper highlight the striking differences between the interactomes of wild‐type and mutant RPS19 proteins. In particular, mutations abolish interactions with proteins having splicing, translational and helicase activity, thus confirming the role of RPS19 in RNA processing/metabolism and translational control. The data have been deposited to the ProteomeXchange with identifier PXD000640 ( http://proteomecentral.proteomexchange.org/dataset/PXD000640 ).     

Monoamine metabolites,iron induced seizures,and the anticonvulsant effect of tannins

Intracortical injections of iron ions have been shown to induce recurrent seizures and epileptic discharges in the EEG. (–)-Epigallocatechin (EGC) and (–)-epigallocatecatechin-3-O-gallate (EGCG), isolated from green tea leaves, have been reported to prevent or diminish the occurrence of epileptic discharges induced by iron ions, and to inhibit catechol-O-methyltransferase. Iron ions significantly increased DOPAC and HVA levels in the intrastriatal perfusate 140 and 180 minutes, respectively, after injection. EGC and EGCG inhibited the increases induced by iron ions. Furthermore, EGCG decreased the HVA level in the perfusate 200 minutes after injection whether or not iron ions were injected. Iron ions had no effect on the 5-HIAA level, and EGC and EGCG raised it. These results suggest that formation of an epileptic focus induced by iron ions might be accompanied by activation of dopaminergic neurons, and that EGC and EGCG inhibit that hyperactivity.     

Lysine methylation modulates the protein–protein interactions of yeast cytochrome C Cyc1p

In recent years, protein methylation has been established as a major intracellular PTM. It has also been proposed to modulate protein‐protein interactions (PPIs) in the interactome. To investigate the effect of PTMs on PPIs, we recently developed the conditional two‐hybrid (C2H) system. With this, we demonstrated that arginine methylation can modulate PPIs in the yeast interactome. Here, we used the C2H system to investigate the effect of lysine methylation. Specifically, we asked whether Ctm1p‐mediated trimethylation of yeast cytochrome c Cyc1p, on lysine 78, modulates its interactions with Erv1p, Ccp1p, Cyc2p and Cyc3p. We show that the interactions between Cyc1p and Erv1p, and between Cyc1p and Cyc3p, are significantly increased upon trimethylation of lysine 78. This increase of interaction helps explain the reported facilitation of Cyc1p import into the mitochondrial intermembrane space upon methylation. This first application of the C2H system to the study of methyllysine‐modulated interactions further confirms its robustness and flexibility.