Pareto Optimality Explanation of the Glycolytic Alternatives in Nature.
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SUBMITTER: Ng CY
PROVIDER: S-EPMC6384925 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAccurate protein loop structure models are important to understand functions of many proteins. Identifying the native or near-native models by distinguishing them from the misfolded ones is a critical step in protein loop structure prediction.ResultsWe have developed a Pareto Optimal Consensus (POC) method, which is a consensus model ranking approach to integrate multiple knowledge- or physics-based scoring functions. The procedure of identifying the models of best quality in a model set includes: 1) identifying the models at the Pareto optimal front with respect to a set of scoring functions, and 2) ranking them based on the fuzzy dominance relationship to the rest of the models. We apply the POC method to a large number of decoy sets for loops of 4- to 12-residue in length using a functional space composed of several carefully-selected scoring functions: Rosetta, DOPE, DDFIRE, OPLS-AA, and a triplet backbone dihedral potential developed in our lab. Our computational results show that the sets of Pareto-optimal decoys, which are typically composed of approximately 20% or less of the overall decoys in a set, have a good coverage of the best or near-best decoys in more than 99% of the loop targets. Compared to the individual scoring function yielding best selection accuracy in the decoy sets, the POC method yields 23%, 37%, and 64% less false positives in distinguishing the native conformation, indentifying a near-native model (RMSD < 0.5A from the native) as top-ranked, and selecting at least one near-native model in the top-5-ranked models, respectively. Similar effectiveness of the POC method is also found in the decoy sets from membrane protein loops. Furthermore, the POC method outperforms the other popularly-used consensus strategies in model ranking, such as rank-by-number, rank-by-rank, rank-by-vote, and regression-based methods.ConclusionsBy integrating multiple knowledge- and physics-based scoring functions based on Pareto optimality and fuzzy dominance, the POC method is effective in distinguishing the best loop models from the other ones within a loop model set.
| S-EPMC2914074 | biostudies-literature
Project description:Graph theory has provided a key mathematical framework to analyse the architecture of human brain networks. This architecture embodies an inherently complex relationship between connection topology, the spatial arrangement of network elements, and the resulting network cost and functional performance. An exploration of these interacting factors and driving forces may reveal salient network features that are critically important for shaping and constraining the brain's topological organization and its evolvability. Several studies have pointed to an economic balance between network cost and network efficiency with networks organized in an 'economical' small-world favouring high communication efficiency at a low wiring cost. In this study, we define and explore a network morphospace in order to characterize different aspects of communication efficiency in human brain networks. Using a multi-objective evolutionary approach that approximates a Pareto-optimal set within the morphospace, we investigate the capacity of anatomical brain networks to evolve towards topologies that exhibit optimal information processing features while preserving network cost. This approach allows us to investigate network topologies that emerge under specific selection pressures, thus providing some insight into the selectional forces that may have shaped the network architecture of existing human brains.
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Project description:When organisms need to perform multiple tasks they face a fundamental tradeoff: no phenotype can be optimal at all tasks. This situation was recently analyzed using Pareto optimality, showing that tradeoffs between tasks lead to phenotypes distributed on low dimensional polygons in trait space. The vertices of these polygons are archetypes--phenotypes optimal at a single task. This theory was applied to examples from animal morphology and gene expression. Here we ask whether Pareto optimality theory can apply to life history traits, which include longevity, fecundity and mass. To comprehensively explore the geometry of life history trait space, we analyze a dataset of life history traits of 2105 endothermic species. We find that, to a first approximation, life history traits fall on a triangle in log-mass log-longevity space. The vertices of the triangle suggest three archetypal strategies, exemplified by bats, shrews and whales, with specialists near the vertices and generalists in the middle of the triangle. To a second approximation, the data lies in a tetrahedron, whose extra vertex above the mass-longevity triangle suggests a fourth strategy related to carnivory. Each animal species can thus be placed in a coordinate system according to its distance from the archetypes, which may be useful for genome-scale comparative studies of mammalian aging and other biological aspects. We further demonstrate that Pareto optimality can explain a range of previous studies which found animal and plant phenotypes which lie in triangles in trait space. This study demonstrates the applicability of multi-objective optimization principles to understand life history traits and to infer archetypal strategies that suggest why some mammalian species live much longer than others of similar mass.
| S-EPMC4605829 | biostudies-literature
Project description:Despite mounting evidence that in clonal bacterial populations, phenotypic variability originates from stochasticity in gene expression, little is known about noise-shaping evolutionary forces and how expression noise translates to phenotypic differences. Here we developed a high-throughput assay that uses a redox-sensitive dye to couple growth of thousands of bacterial colonies to their respiratory activity and show that in Escherichia coli, noisy regulation of lower glycolysis and citric acid cycle is responsible for large variations in respiratory metabolism. We found that these variations are Pareto optimal to maximization of growth rate and minimization of lag time, two objectives competing between fermentative and respiratory metabolism. Metabolome-based analysis revealed the role of respiratory metabolism in preventing the accumulation of toxic intermediates of branched chain amino acid biosynthesis, thereby supporting early onset of cell growth after carbon starvation. We propose that optimal metabolic tradeoffs play a key role in shaping and preserving phenotypic heterogeneity and adaptation to fluctuating environments.
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Project description:Mutations in the park2 gene, encoding the RING-inBetweenRING-RING E3 ubiquitin ligase parkin, cause 50% of autosomal recessive juvenile Parkinsonism cases. More than 70 known pathogenic mutations occur throughout parkin, many of which cluster in the inhibitory amino-terminal ubiquitin-like domain, and the carboxy-terminal RING2 domain that is indispensable for ubiquitin transfer. A structural rationale showing how autosomal recessive juvenile Parkinsonism mutations alter parkin function is still lacking. Here we show that the structure of parkin RING2 is distinct from canonical RING E3 ligases and lacks key elements required for E2-conjugating enzyme recruitment. Several pathogenic mutations in RING2 alter the environment of a single surface-exposed catalytic cysteine to inhibit ubiquitination. Native parkin adopts a globular inhibited conformation in solution facilitated by the association of the ubiquitin-like domain with the RING-inBetweenRING-RING C-terminus. Autosomal recessive juvenile Parkinsonism mutations disrupt this conformation. Finally, parkin autoubiquitinates only in cis, providing a molecular explanation for the recessive nature of autosomal recessive juvenile Parkinsonism.
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Project description:While much prior literature on the meaning of clefts-such as the English form "it is X who Z-ed"-concentrates on the nature and status of the exhaustivity inference ("nobody/nothing other than X Z"), we report on experiments examining the role of the doxastic status of alternatives on the naturalness of c'est-clefts in French and it-clefts in English. Specifically, we study the hypothesis that clefts indicate a conflict with a doxastic commitment held by some discourse participant. Results from naturalness tasks suggest that clefts are improved by a property we term "contrariness" (along the lines of Zimmermann, 2008). This property has a gradient effect on felicity judgments: the more strongly interlocutors appear committed to an apparently false notion, the better it is to repudiate them with a cleft.
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Project description:Organisms adjust their gene expression to improve fitness in diverse environments. But finding the optimal expression in each environment presents a challenge. We ask how good cells are at finding such optima by studying the control of carbon catabolism genes in Escherichia coli. Bacteria show a growth law: growth rate on different carbon sources declines linearly with the steady-state expression of carbon catabolic genes. We experimentally modulate gene expression to ask if this growth law always maximizes growth rate, as has been suggested by theory. We find that the growth law is optimal in many conditions, including a range of perturbations to lactose uptake, but provides sub-optimal growth on several other carbon sources. Combining theory and experiment, we genetically re-engineer E. coli to make sub-optimal conditions into optimal ones and vice versa. We conclude that the carbon growth law is not always optimal, but represents a practical heuristic that often works but sometimes fails.
| S-EPMC5253639 | biostudies-literature
Project description:Riboswitches are RNA elements that recognize diverse chemical and biomolecular inputs, and transduce this recognition process to genetic, fluorescent, and other engineered outputs using RNA conformational changes. These systems are pervasive in cellular biology and are a promising biotechnology with applications in genetic regulation and biosensing. Here, we derive a simple expression bounding the activation ratio-the proportion of RNA in the active vs. inactive states-for both ON and OFF riboswitches that operate near thermodynamic equilibrium: 1+[I]/KdI, where [I] is the input ligand concentration and KdI is the intrinsic dissociation constant of the aptamer module toward the input ligand. A survey of published studies of natural and synthetic riboswitches confirms that the vast majority of empirically measured activation ratios have remained well below this thermodynamic limit. A few natural and synthetic riboswitches achieve activation ratios close to the limit, and these molecules highlight important principles for achieving high riboswitch performance. For several applications, including "light-up" fluorescent sensors and chemically-controlled CRISPR/Cas complexes, the thermodynamic limit has not yet been achieved, suggesting that current tools are operating at suboptimal efficiencies. Future riboswitch studies will benefit from comparing observed activation ratios to this simple expression for the optimal activation ratio. We present experimental and computational suggestions for how to make these quantitative comparisons and suggest new molecular mechanisms that may allow non-equilibrium riboswitches to surpass the derived limit.
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Project description:Computer-assisted design of small molecules has experienced a resurgence in academic and industrial interest due to the widespread use of data-driven techniques such as deep generative models. While the ability to generate molecules that fulfil required chemical properties is encouraging, the use of deep learning models requires significant, if not prohibitive, amounts of data and computational power. At the same time, open-sourcing of more traditional techniques such as graph-based genetic algorithms for molecular optimisation [Jensen, Chem. Sci., 2019, 12, 3567-3572] has shown that simple and training-free algorithms can be efficient and robust alternatives. Further research alleviated the common genetic algorithm issue of evolutionary stagnation by enforcing molecular diversity during optimisation [Van den Abeele, Chem. Sci., 2020, 42, 11485-11491]. The crucial lesson distilled from the simultaneous development of deep generative models and advanced genetic algorithms has been the importance of chemical space exploration [Aspuru-Guzik, Chem. Sci., 2021, 12, 7079-7090]. For single-objective optimisation problems, chemical space exploration had to be discovered as a useable resource but in multi-objective optimisation problems, an exploration of trade-offs between conflicting objectives is inherently present. In this paper we provide state-of-the-art and open-source implementations of two generations of graph-based non-dominated sorting genetic algorithms (NSGA-II, NSGA-III) for molecular multi-objective optimisation. We provide the results of a series of benchmarks for the inverse design of small molecule drugs for both the NSGA-II and NSGA-III algorithms. In addition, we introduce the dominated hypervolume and extended fingerprint based internal similarity as novel metrics for these benchmarks. By design, NSGA-II, and NSGA-III outperform a single optimisation method baseline in terms of dominated hypervolume, but remarkably our results show they do so without relying on a greater internal chemical diversity.
| S-EPMC9241971 | biostudies-literature
Project description:Curved rods are a ubiquitous bacterial phenotype, but the fundamental question of why they are shaped this way remains unanswered. Through in silico experiments, we assessed freely swimming straight- and curved-rod bacteria of a wide diversity of equal-volume shapes parameterized by elongation and curvature, and predicted their performances in tasks likely to strongly influence overall fitness. Performance trade-offs between these tasks lead to a variety of shapes that are Pareto-optimal, including coccoids, all straight rods, and a range of curvatures. Comparison with an extensive morphological survey of motile curved-rod bacteria indicates that the vast majority of species fall within the Pareto-optimal region of morphospace. This result is consistent with evolutionary trade-offs between just three tasks: efficient swimming, chemotaxis, and low cell construction cost. We thus reveal the underlying selective pressures driving morphological diversity in a widespread component of microbial ecosystems.
| S-EPMC6642390 | biostudies-literature