Rigidity and flexibility of biological networks

The network approach became a widely used tool to understand the behaviour of complex systems in the last decade. We start from a short description of structural rigidity theory. A detailed account on the combinatorial rigidity analysis of protein structures, as well as local flexibility measures of proteins and their applications in explaining allostery and thermostability is given. We also briefly discuss the network aspects of cytoskeletal tensegrity. Finally, we show the importance of the balance between functional flexibility and rigidity in protein-protein interaction, metabolic, gene regulatory and neuronal networks. Our summary raises the possibility that the concepts of flexibility and rigidity can be generalized to all networks.Comment: 21 pages, 4 figures, 1 tabl

Quantitative Analysis of the Effective Functional Structure in Yeast Glycolysis

Yeast glycolysis is considered the prototype of dissipative biochemical oscillators. In cellular conditions, under sinusoidal source of glucose, the activity of glycolytic enzymes can display either periodic, quasiperiodic or chaotic behavior. In order to quantify the functional connectivity for the glycolytic enzymes in dissipative conditions we have analyzed different catalytic patterns using the non-linear statistical tool of Transfer Entropy. The data were obtained by means of a yeast glycolytic model formed by three delay differential equations where the enzymatic speed functions of the irreversible stages have been explicitly considered. These enzymatic activity functions were previously modeled and tested experimentally by other different groups. In agreement with experimental conditions, the studied time series corresponded to a quasi-periodic route to chaos. The results of the analysis are three-fold: first, in addition to the classical topological structure characterized by the specific location of enzymes, substrates, products and feedback regulatory metabolites, an effective functional structure emerges in the modeled glycolytic system, which is dynamical and characterized by notable variations of the functional interactions. Second, the dynamical structure exhibits a metabolic invariant which constrains the functional attributes of the enzymes. Finally, in accordance with the classical biochemical studies, our numerical analysis reveals in a quantitative manner that the enzyme phosphofructokinase is the key-core of the metabolic system, behaving for all conditions as the main source of the effective causal flows in yeast glycolysis.Comment: Biologically improve

Edge vulnerability in neural and metabolic networks

Biological networks, such as cellular metabolic pathways or networks of corticocortical connections in the brain, are intricately organized, yet remarkably robust toward structural damage. Whereas many studies have investigated specific aspects of robustness, such as molecular mechanisms of repair, this article focuses more generally on how local structural features in networks may give rise to their global stability. In many networks the failure of single connections may be more likely than the extinction of entire nodes, yet no analysis of edge importance (edge vulnerability) has been provided so far for biological networks. We tested several measures for identifying vulnerable edges and compared their prediction performance in biological and artificial networks. Among the tested measures, edge frequency in all shortest paths of a network yielded a particularly high correlation with vulnerability, and identified inter-cluster connections in biological but not in random and scale-free benchmark networks. We discuss different local and global network patterns and the edge vulnerability resulting from them.Comment: 8 pages, 4 figures, to appear in Biological Cybernetic

New synthetic biology tools for metabolic control

In industrial bioprocesses, microbial metabolism dictates the product yields, and therefore, our capacity to control it has an enormous potential to help us move towards a bio-based economy. The rapid development of multiomics data has accelerated our systematic understanding of complex metabolic regulatory mechanisms, which allow us to develop tools to manipulate them. In the last few years, machine learning-based metabolic modeling, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) derived synthetic biology tools, and synthetic genetic circuits have been widely used to control the metabolism of microorganisms, manipulate gene expression, and build synthetic pathways for bioproduction. This review describes the latest developments for metabolic control, and focuses on the trends and challenges of metabolic engineering strategies

A mechanism-aware and multiomic machine-learning pipeline characterizes yeast cell growth

Metabolic modeling and machine learning are key components in the emerging next generation of systems and synthetic biology tools, targeting the genotype–phenotype–environment relationship. Rather than being used in isolation, it is becoming clear that their value is maximized when they are combined. However, the potential of integrating these two frameworks for omic data augmentation and integration is largely unexplored. We propose, rigorously assess, and compare machine-learning–based data integration techniques, combining gene expression profiles with computationally generated metabolic flux data to predict yeast cell growth. To this end, we create strain-specific metabolic models for 1,143 Saccharomyces cerevisiae mutants and we test 27 machine-learning methods, incorporating state-of-the-art feature selection and multiview learning approaches. We propose a multiview neural network using fluxomic and transcriptomic data, showing that the former increases the predictive accuracy of the latter and reveals functional patterns that are not directly deducible from gene expression alone. We test the proposed neural network on a further 86 strains generated in a different experiment, therefore verifying its robustness to an additional independent dataset. Finally, we show that introducing mechanistic flux features improves the predictions also for knockout strains whose genes were not modeled in the metabolic reconstruction. Our results thus demonstrate that fusing experimental cues with in silico models, based on known biochemistry, can contribute with disjoint information toward biologically informed and interpretable machine learning. Overall, this study provides tools for understanding and manipulating complex phenotypes, increasing both the prediction accuracy and the extent of discernible mechanistic biological insights

Receptor uptake arrays for vitamin B12, siderophores and glycans shape bacterial communities

Molecular variants of vitamin B12, siderophores and glycans occur. To take up variant forms, bacteria may express an array of receptors. The gut microbe Bacteroides thetaiotaomicron has three different receptors to take up variants of vitamin B12 and 88 receptors to take up various glycans. The design of receptor arrays reflects key processes that shape cellular evolution. Competition may focus each species on a subset of the available nutrient diversity. Some gut bacteria can take up only a narrow range of carbohydrates, whereas species such as B.~thetaiotaomicron can digest many different complex glycans. Comparison of different nutrients, habitats, and genomes provide opportunity to test hypotheses about the breadth of receptor arrays. Another important process concerns fluctuations in nutrient availability. Such fluctuations enhance the value of cellular sensors, which gain information about environmental availability and adjust receptor deployment. Bacteria often adjust receptor expression in response to fluctuations of particular carbohydrate food sources. Some species may adjust expression of uptake receptors for specific siderophores. How do cells use sensor information to control the response to fluctuations? That question about regulatory wiring relates to problems that arise in control theory and artificial intelligence. Control theory clarifies how to analyze environmental fluctuations in relation to the design of sensors and response systems. Recent advances in deep learning studies of artificial intelligence focus on the architecture of regulatory wiring and the ways in which complex control networks represent and classify environmental states. I emphasize the similar design problems that arise in cellular evolution, control theory, and artificial intelligence. I connect those broad concepts to testable hypotheses for bacterial uptake of B12, siderophores and glycans.Comment: Added many new references, edited throughou

An outlook on metabolic pathway engineering in crop plants

To produce the essential secondary metabolites, plants are the major and important target source materials for conducting the high-profile metabolic engineering studies. Metabolic pathway engineering of both microorganism targets and plants target contribute towards important drug discovery. In order to efficiently work out in advanced plant metabolic pathway engineering techniques, a detailed knowledge and expertise is essentially needed regarding the plant cell physiology and the mechanics of plant metabolism. Mathematical and statistical models to scale and map the genome for integrative metabolic pathway activity, signal transduction mechanism in the genome, gene regulation and the networks of protein-protein interaction can provide the in-depth knowledge to work efficiently on plant metabolic pathway engineering studies. Incorporation of omics data into these statistical and mathematical models is crucial in the case of drug discovery using the plant system. Recently, artificial intelligence concept and approaches are experimentally applied for efficient and accurate metabolic engineering in plants

Decoding Complexity in Metabolic Networks using Integrated Mechanistic and Machine Learning Approaches

How can we get living cells to do what we want? What do they actually ‘want’? What ‘rules’ do they observe? How can we better understand and manipulate them? Answers to fundamental research questions like these are critical to overcoming bottlenecks in metabolic engineering and optimizing heterologous pathways for synthetic biology applications. Unfortunately, biological systems are too complex to be completely described by physicochemical modeling alone. In this research, I developed and applied integrated mechanistic and data-driven frameworks to help uncover the mysteries of cellular regulation and control. These tools provide a computational framework for seeking answers to pertinent biological questions. Four major tasks were accomplished. First, I developed innovative tools for key areas in the genome-to-phenome mapping pipeline. An efficient gap filling algorithm (called BoostGAPFILL) that integrates mechanistic and machine learning techniques was developed for the refinement of genome-scale metabolic network reconstructions. Genome-scale metabolic network reconstructions are finding ever increasing applications in metabolic engineering for industrial, medical and environmental purposes. Second, I designed a thermodynamics-based framework (called REMEP) for mutant phenotype prediction (integrating metabolomics, fluxomics and thermodynamics data). These tools will go a long way in improving the fidelity of model predictions of microbial cell factories. Third, I designed a data-driven framework for characterizing and predicting the effectiveness of metabolic engineering strategies. This involved building a knowledgebase of historical microbial cell factory performance from published literature. Advanced machine learning concepts, such as ensemble learning and data augmentation, were employed in combination with standard mechanistic models to develop a predictive platform for important industrial biotechnology metrics such as yield, titer, and productivity. Fourth, my modeling tools and skills have been used for case studies on fungal lipid metabolism analyses, E. coli resource allocation balances, reconstruction of the genome-scale metabolic network for a non-model species, R. opacus, as well as the rapid prediction of bacterial heterotrophic fluxomics. In the long run, this integrated modeling approach will significantly shorten the “design-build-test-learn” cycle of metabolic engineering, as well as provide a platform for biological discovery